Device and method for altering neurotransmitter level in brain

ABSTRACT

The present disclosure relates to a device and a method for non-invasively applying optical radiation to photosensitive parts of the brain. In particular the present invention is directed to a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in altering and/or controlling the production, release, re-uptake and/or metabolism of dopamine or serotonin in at least one of said one or more neuroanatomical brain structures and/or in the body of the user.

The present invention relates to a device and a method for non-invasively applying optical radiation to photosensitive parts of the brain.

BACKGROUND OF INVENTION

It is well known that light has a direct effect on human health because of the way it influences the circadian rhythm. And the human (and animal) brain includes regions that can be affected by optical radiation. This may result in a metabolic or nervous responsive stimulation, which may appear as a change in concentrations of several hormones and neuro-transmitters. The light may be natural sunlight but also artificial light sources are known to have an effect. The hormone melatonin is secreted in the pineal gland as a response to light and helps to control the circadian rhythm. Secretion of melatonin peaks at night and ebbs during the day and its presence provides information about night-length. Disruption of the circadian rhythm, e.g. due to lack of daylight or crossing time zones, usually has a negative effect and may lead to jet lag, bipolar disorders and circadian rhythm sleep disorders such as seasonal affective disorder (SAD) and delayed sleep phase syndrome (DSPS). In addition most mood disorders and many neurological disorders have a pattern of symptomality changing in accordance to annual rhythm.

It is typically necessary to use artificial optical radiation when natural light is not sufficient for achieving a desired physiological effect. Artificial optical radiation may be generated by bright light therapy devices in the form of the well-known bright light lamps where a person, and especially the face, is exposed to bright light, whereby the light is believed to be transported into the brain via the ocular route i.e. through the eyes. The drawback of this conventional light therapy is that the amount of light required may be so high that delivering it via the ocular route may cause damage to the eye nerve, headache and other harmful side effects. Another drawback is that the recommended treatment time is at least half an hour, and preferably at least one hour, which limits a person's daily life. The person should also be very close to the light device to realize a therapeutic effect, preferably as close as 10-20 inches (30-50 cm), which makes administration cumbersome. Traditional light therapy lamps also must produce 2,500-10,000 lux, making these light units very high in energy consumption.

Alternative routes for light therapy have been proposed. However, the knowledge of their effect is very limited and clinical evidence on treatment modalities like dosing or clinical intensities that would be needed for effective treatment have not been studied. WO98/51372 discloses a method of resetting the circadian clock by applying non-solar photic stimulation of 15 to 150,000 lux, preferably 10,000 to 13,000 lux to any non-ocular region of the human body for 15 minutes to about 12 hours, preferably for 3 hours. Such treatment is hard to carry out without affecting normal activity. Recently a more elegant solution has been commercialized in the form of the Valkee Brain Stimulation Headset described in WO 2008/029001 wherein bright light LED (Light Emitting Diode) light is provided to the brain through the auditory canal. WO 2008/029001 is hereby incorporated by reference in its entirety.

SUMMARY OF INVENTION

In general the present invention relates to a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures from an extra-cranial position of a user. In particular the device according to the invention may be applied for use in altering and/or controlling the production, release, re-uptake and/or metabolism of serotonin, dopamine and/or noradrenaline in at least one of said one or more neuroanatomical brain structures and/or in the body of the user.

In order to avoid absorption in the cerebrum the device and/or the radiation unit(s) may be adapted to direct the optical radiation from at least one extra-cranial position below the cerebrum of the user. Said at least one extra-cranial position is preferably non-ocular, i.e. the optical radiation is preferably not provided through the eyes of the user. The device may comprise a housing in optical and/or electrical connection with said one or more radiation units. Further, the device may comprise one or more light sources, e.g. LED's, for generating the optical radiation. The device may comprise means for adapting the intensity of the optical radiation, such as electronic control means, e.g. situated in the housing, for adjusting the power supplied to the light sources. The device may further comprise means for adapting the spectral composition of the optical radiation. For some types of light sources the spectral composition of the emitted light may be changed by varying the temperature or power of applying different types of filters or phosphorizing elements in the light path. The spectral composition may also be varied by combining different light sources with different spectral compositions and independently controlling the different light sources. The optical radiation emitted from a radiation unit may be applied with a predefined setting, e.g. the optical radiation (continuous wave (CW) or pulsed) may be applied with one or more of the following parameters being predefined: duration, intensity, pulse frequency, total power and spectral composition.

A problem with light therapy is therefore that little is known about the dose of light needed to achieve a therapeutic effect without harmful side effects, as it has been difficult to administer an accurate dose. Lack of accurate administration has led to varying clinical trial results, and for example FDA being skeptical on approving light therapy devices. Another problem is that little is known about which routes of light treatment are effective. A further aspect of the invention is therefore directed to a medical device comprising radiation means for directing light via the ear canal of a subject for use in light therapy comprising non-invasive intra-cranial administration of bright light using a luminous flux of 0.7-12 lumens for 1-15 minutes. The present invention is also directed to a method of treating a subject in need of light therapy, the method comprising the steps of: providing a medical device comprising radiation means for directing light via the ear canal of the subject, applying the device to the subject, and directing non-invasively, intra-cranially via the subject's ear canal bright light having an luminous flux of 0.7-12 lumens for a treatment time of 1-15 minutes.

DESCRIPTION OF DRAWINGS

FIG. 1 a is a cross-sectional side view illustration of the human brain pointing out different neuro-anatomical brain structures and serotonin pathways.

FIG. 1 b shows a cross-sectional schematic diagram of the human brain illustrating specific neuro-anatomical regions and serotonin pathways.

FIG. 2 shows normalized absorption spectra of various opsins.

FIG. 3 shows measured relative amounts of OPN3 and OPN4 in different regions of the human brain.

FIG. 4 is a cross-sectional side view illustration of the human brain showing the dopamine pathyways.

FIG. 5 shows an illustration of how light can be distributed to photosensitive regions in the brain via the auditory canal.

FIG. 6 show frontal and cross-sectional side view illustrations of a human head where the size of the cerebrum is indicated.

FIG. 7 a)-f) show possible placements and different embodiments of the device according to the invention.

FIG. 8 a shows an exemplary spectral composition of a white LED.

FIG. 8 b shows the spectral LED composition of FIG. 8 a where the spectral output in three different wavelength intervals are indicated.

FIG. 8 c shows the spectral composition of four different LEDs and their combined spectral composition.

FIG. 9 shows top and side view schematic illustrations of an example of a (part of a) radiation unit with four different light sources.

FIG. 10 is a schematic illustration of a high level architecture of a network system incorporating a device according to the invention.

FIG. 11 shows three different spectral compositions, each having two intensity peaks but with different ratios of spectral outputs integrated around each peak.

FIG. 12 shows the procedure of a controlled dose-response study of transcranial light therapy disclosed in example 1.

FIG. 13 shows response rates measured by SIGH-SAD, HAMA and BDI in different treatment groups in the light therapy dose-response study.

FIG. 14 shows BDI sum scores in different treatment groups during the four-week treatment period of the light therapy dose-response study.

FIGS. 15A-E show various spectral compositions of LED's of certain types.

FIGS. 16A-B show measured progress for type A and type B trail making test for test persons which have been subject to trans-cranial light therapy (see examples 6 and 7).

FIGS. 17A-D show measured reaction time to auditory and visual stimulus for two groups of test persons (see example 8).

FIGS. 18A-B show the improvement in reaction time for the two groups (see example 8).

FIG. 19 shows Hamilton Depression Scale (HAMD-17) and Beck Depression Inventory (BDI-21) scores in human subjects treated by intra-cranial brain-targeted bright light via the ear canals (example 12).

FIG. 20 a shows the set-up for light stimulus and sham controls during fMRI scanning (example 10).

FIG. 20 b shows sections from MNI152 T1 standard space brain template illustrating the brain regions presumably encountering the main light cone beam (example 10).

FIG. 21 a shows that there is greater functional connectivity in the light stimulus group compared to controls (example 10).

FIG. 21 b shows temporal characteristics of the lateral visual component of the light group (upper darkest curve) and the corresponding control group curve (lower curve) (example 10).

FIG. 21 c shows the corresponding frequency representation of FIG. 21 b with group mean and standard deviation, light group (upper darkest curve) and control group curve (lower curve) (example 10).

FIG. 22 a shows that there is greater functional connectivity in the light stimulus group compared to controls (example 10).

FIG. 22 b shows temporal characteristics of the sensorimotor independent component of the light group (darkest curve) and the corresponding control group curve (example 10).

FIG. 22 c shows the corresponding frequency representation of FIG. 22 b with group mean and standard deviation, light group (upper darkest curve) and control group curve (lower curve) (example 10).

DEFINITIONS

Disease as used herein is an abnormal condition of an organism that impairs bodily functions, associated with specific symptoms and signs, typically causes discomfort and/or dysfunction. Herein used interchangeably with disorder.

Disorder as used herein is a functional abnormality or disturbance. Herein used interchangeably with disease

Opsins (OPN) are light-sensing proteins belonging to the superfamily of G-protein-coupled receptors (GPCR). Opsins are known to mediate phototransduction in both visual and nonvisual systems by being transmembrane receptorproteins. Main principle of action for these receptors is to activate a guanine nucleotide binding protein (Gprotein) and an effector enzyme to produce response in the attached cell. Based on sequence homology, opsins can be distinguished in to six subfamilies: vertebrate opsin/encephalopsin, Go, Gs, Gq, photoisomerase and neuropsin subfamilies. On the basis of cellular expression/function and phylogeny, the classification has three categories—ciliary opsins, rhabdomeric opsins and photoisomerases. According to the name, ciliary opsins are thought to localise in ciliary photoreceptor cells, rhabdomeric opsins in rhabdomeric photoreceptor cells, whereas photoisomerases are a group of opsins sharing same phylogeny and intron positions.

FIG. 4 shows measured relative amounts of OPN3 (left column) and OPN4 (right column) in different neuro-anatomical structures/regions of the human brain.

TABLE 1 Chromosomal locations and number of introns of the nine human opsin genes. Opsin Chromosomal location Number of introns Rhodopsin 3q22.l 4 Blue opsin 7q32.l 4 Red opsin Xq28 5 Green opsin Xq28 5 Encephalopsin lq43 3 Melanopsin l0q23.2 9 Peropsin 4q25 6 RGR l0q23.l 6 Neuropsin 6pl2.3 6

Phototransduction is a process by which light is converted into electrical signals in the rod cells, cone cells and photosensitive ganglion cells of the retina of the eye. In general, all known vertebrate photoreceptors use an opsin protein bound to a vitamin A-chromophore as photopigment. Over species and opsins, the principle of phototransduction is always the same: When the photon is absorbed by the retinal chromophore, this molecule isomerizes from 11-cis-retinal form to the all-trans-retinal form. This conformational change allows opsin-proteins intracellular terminus to trigger a G-protein cascade leading into rise in receptor membrane potential. Phototransduction is this cascade converting photic energy into neural responses. In addition phototransduction may cover also reactions on receptors and chemical compounds called excitatory aminoacids (e.g. glutamate receptor), when said receptors may have allosterical regulation due to illumination. This phenomena at least partly overlaps and coincides the opsin-mediated phototransduction and may also participate to the release of neurotransmitters, monoamines, psychogenic amines, GABA, NMDA and several other messengers affecting to the signal transduction in the brain and elsewhere in the CNS. Conceptually, the same cascade, as in the eye, happens on the neural cells of the brain when opsins are absorbing photons. In addition in this document phototransduction mostly refers to relatively slow and modulatory changes in the membrane potential.

Diseases and Disorders Relating to Chemical Imbalances Mental Diseases

A mental disorder or mental illness is a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. For example a depressed mood is often reported as feeling sad, helpless, and hopeless.

Parkinson's Disease

(also known as Parkinson disease, Parkinson's, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra. The aetiology is considered to be different mechanisms of cellular damage in substantia nigra. The damage might be related to cell death caused by inflammation. The inflammation and cell death may also be caused by autoimmune routes, also different heavy-metal poisonings might be the reason for autolysis of substantia nigra regions, having immunoreaction central in its mechanism.

A particular conceptual model of the motor circuit and its alteration with Parkinson's disease has been of great influence. In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in Parkinson's disease, demands greater exertions of effort for any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. There is presently no cure for Parkinson's disease, but medications, surgery and multidisciplinary management can provide relief from the symptoms.

The main families of drugs useful for treating motor symptoms are levodopa, dopamine agonists and MAO-B inhibitors. Levodopa has been the most widely used treatment for over 30 years. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of Levodopa temporarily diminishes the motor symptoms. Levodopa is converted into dopamine in the dopaminergic neurons by dopa decarboxylase but only 5-10% of Levodopa actually crosses the blood-brain barrier. The remainder is often metabolized to dopamine elsewhere, thus possibly producing excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias, marked by involuntary writhing movements, and other side effects including nausea and joint stiffness. The drug based treatments are effective at managing the early motor symptoms of the disease. As the disease progresses and dopamine neurons continue to be lost, a point eventually arrives at which these drugs become ineffective at treating the symptoms and at the same time produce dyskinesia.

Tobacco smokers' risk of having Parkinson's disease may be reduced down to a third when compared to non-smokers. The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.

Obsessive-Compulsive Disorder (OCD)

is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviours aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions. Imbalance of brain chemicals, especially serotonin and dopamine, may contribute to OCD. Independent studies have consistently found unusual dopamine and serotonin activity in various regions of the brain in individuals with OCD. These can be defined as dopaminergic hyperfunction in the prefrontal cortex and serotonergic hypofunction in the basal ganglia.

Alcohol Addiction

Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages. It is medically considered a neurological disorder. Alcohol causes the body to release endorphins, which in turn release dopamine and activate the reward pathways.

Tobacco and Nicotine Addiction

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphin. This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems. Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the Mesolimbic pathway (“reward system”)—the circuitry within the brain that regulates feelings of pleasure and euphoria. By increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. Like other physically addictive drugs, nicotine withdrawal causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation.

Seasonal Affective Disorder (SAD)

SAD is considered as a sub-type of recurrent MDD, a sub-type of bipolar affective disorder in which depressive episodes regularly begin in one season and remit in another season, or as a sub-type of atypical depression characterized by mood reactivity and being able to experience improved mood in response to positive events. The winter-type of SAD manifests as atypical symptoms of depression that recur in the fall and winter, such as depressed mood, anhedonia, decreased activity, decreased libido, hyperphagia, hypersomnia, carbohydrate carving, fatigue and weight gain. It is believed possible that functional connectivity alterations related to SAD exist in brain regions earlier reported to involve metabolic changes in SAD patients. Epidemiological studies conclude that any population living above 30 degrees northern latitude, or below 30 degrees southern latitude have seasonal symptoms, and that in the US the prevalence correlates to the latitude. Persons suffering from SAD may be conveniently treated with the above described light therapy. Typically light having a luminous flux of 3-9 lumens is administered for 6-12 minutes at least once a day for at least five days a week during the season when SAD is symptomatic.

Migraine

The typical migraine headache is unilateral pain (affecting one half of the head) and pulsating in nature, lasting from 4 to 72 hours; symptoms include nausea, vomiting, photophobia (increased sensitivity to light), phonophobia (increased sensitivity to sound), and is aggravated by routine activity. Approximately one-third of people who suffer from migraine headaches perceive an aura-unusual visual, olfactory, or other sensory experiences that are a sign that the migraine will soon occur. People suffering from migraine constitute another group of patients that are responsive to light therapy according to the present invention. It is indeed remarkable that bright light administered intra-cranially via a non-ocular route can prevent migraine attacks or stop an already arousing migraine attack, because generally exposure to bright light via the eyes is considered as a major migraine-triggering factor. Typically light having a luminous flux of 3-9 lumens is administered for 6-12 minutes once a day to prevent migraine, or 1-6 times daily to relieve a migraine attack.

DETAILED DESCRIPTION OF INVENTION Device

The inventors have realized that stimulation of light sensitive regions in the brain does not have to be provided through the ear-canal. The inventors have also realized that stimulation of light sensitive regions in the brain does not have to be provided through the eyes, i.e. the stimulation can be provided non-ocular. The light penetrates quite easily the skull. However, many of the important brain structures are located at or near the brain stem near the center of the head and in order to reach them by light from outside the nature of the incidence of the emitted light is important. Experiments have shown that light applied at the skull from a position approx. above the “equatorial line” of the head formed by the cerebrum of the brain does not necessarily reach the crucial regions the brain because the light is absorbed by the cerebrum, most probably absorbed by the “gray mass” of the cerebral cortex constituting the outermost neural tissue of the cerebrum. One of the reasons for the absorption is blood, the most capable absorber of the light. This is one of the reasons why abundant microvasculature on the cortical areas on the top and sides of the cerebrum is reducing the amount of light penetrating into deep parts of the brain. In order to illuminate these brain regions the light can be incident on the head in a position approx. at the lower line formed by the cerebrum or below this line. Please note that this line following the lower part of the cerebrum is not a straight line as seen in FIG. 6. In another embodiment of the invention the light must be incident on the head in a position approx. at or below Reid's base line.

By conducting experiments on preserved human brains donated from deceased subjects the inventors have been able to measure the presence and amount of various light sensitive opsins in different parts of the human brain. The inventors have thereby realized that because the relative and absolute amounts of specific light sensitive opsins vary in different neuro-anatomical structures of the human brain the reaction in and response of a specific neuro-anatomical brain structure when illuminated with optical radiation is depending on the nature of the radiation, i.e. the nature of the light has a marked influence on the reaction/stimulation pattern in the brain. In particular the spectral composition of the light seems to be important, because as the example illustrated in FIG. 3 for OPN3 and OPN4 the absolute and relative amounts of OPN3 and OPN4 vary for the different brain structures, and as OPN3 and OPN4 has different absorption wavelengths the reaction in a specific brain region will depend on wavelength composition of the light. A first aspect of the invention therefore relates to a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures of a user from at least one extra-cranial position below the cerebrum of the user, wherein the optical radiation emitted from a radiation unit is applied with one or more of the following parameters being predefined for a plurality of predefined wavelength intervals: duration, intensity, total power, spectral output and spectral composition, and wherein the optical radiation emitted from a radiation unit is applied with a predefined ratio of: a first spectral output integrated over a first wavelength interval, and a second spectral output integrated over a second wavelength interval.

Natural bright sunlight at noon (about 80,000-150,000 lux) far exceeds the amount which is normally emitted by conventional bright light lamps (2,500-10,000 lux). The relatively low illuminations derived from conventional light devices reach deep structures of the brain mainly visually, but only to some extent by penetrating via other routes. An advantage of the device according to the present invention is that the photic energy penetrating the skull far exceeds the amount which is normally visibly tolerable and emitted by conventional bright light lamps.

In a further embodiment of the invention the optical radiation emitted from a radiation unit is applied with predefined ratios of: a first spectral output integrated over a first wavelength interval, a second spectral output integrated over a second wavelength interval, and a third spectral output integrated over a third wavelength interval.

In one embodiment of the invention the spectral composition of the optical radiation is adapted to the absorption spectrum of one or more light sensitive opsins. Preferably at least one of said opsins is present in at least one of said neuro-anatomical structures.

In one embodiment of the invention the optical radiation comprises light from a plurality of wavelength intervals. E.g. if the light emitted from a radiation unit is composed of light from different light sources with different wavelength characteristics. Preferably means for adapting the intensity, timing, total power and/or total energy of optical radiation provided in each wavelength interval are then provided. And further means for adapting the ratio of the intensity, timing, total power and/or total energy of optical radiation provided in the wavelength intervals are also preferably provided.

In one embodiment of the invention the optical radiation comprises light in a first wavelength interval with a start point of between 380 nm and 440 nm, such as 385 nm, 390 nm, 395 nm, 400 nm, 405 nm, 410 nm, 415 nm, 420 nm, 425 nm, 430 nm or 435 nm, and an endpoint of between 445 nm and 530 nm, such as 450 nm, 455 nm, 460 nm, 465 nm, 470 nm, 475 nm, 480 nm, 485 nm, 495 nm, 500 nm, 505 nm, 510 nm, 515 nm, 520 nm or 520 nm.

In one embodiment of the invention the optical radiation comprises light in a second wavelength interval with a start point of between 460 nm and 520 nm, such as 465 nm, 470 nm, 475 nm, 480 nm, 485 nm, 490 nm, 500 nm, 505 nm, 510 nm, or 515 nm, and an endpoint of between 590 nm and 800 nm, such as 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm, 780 nm or 790 nm.

In one embodiment of the invention the optical radiation comprises light with a predefined ratio of a first spectral output in a first wavelength interval and a second spectral output in a second wavelength interval. Said predefined ratio may be between 0.1 and 1, such as between 0.1 and 0.15, such as between 0.15 and 0.2, such as between 0.2 and 0.25, such as between 0.25 and 0.3, such as between 0.3 and 0.35, such as between 0.35 and 0.4, such as between 0.4 and 0.45, such as between 0.45 and 0.5, such as between 0.5 and 0.35, such as between 0.55 and 0.6, such as between 0.6 and 0.65, such as between 0.65 and 0.7, such as between 0.7 and 0.75, such as between 0.75 and 0.8, such as between 0.8 and 0.85, such as between 0.85 and 0.9, such as between 0.9 and 0.95, such as between 0.95 and 1.

In one embodiment of the invention the optical radiation is generated by a plurality of different light sources, such as a plurality of light sources with different spectral characteristics. The spectral composition of the optical radiation emitted from the radiation unit(s) can then be adapted by controlling the light sources independently.

In a further embodiment of the invention the radiation unit comprises one or more elements and/or layers of one or more phosphorizing compounds. The principle of a white LED may be used for creating different spectral characteristics. E.g. one or more LED's may be arranged behind different phosphorizing layers, the resulting spectrum is depending on the nature (e.g. composition, thickness, etc.) of the specific phosphorizing layer.

Light sources for generating the optical radiation may be accommodated in a housing of the device. With an optical connection to the radiation unit(s) the light may be distributed for illumination of the user.

In another embodiment of the invention one or more light sources are accommodated in each radiation unit.

In yet another embodiment of the invention each radiation unit comprises a single light source. If there is a plurality of radiation units, each having a single light source, there may be a plurality of different light sources with different wavelength characteristics. The specific single light source is preferably chosen to have a spectral characteristic suitable for one or more specific medical treatments. The radiation units may then be “paired”, i.e. there may be a plurality of paired radiation unit having the same type of light source. Then there can be a pair of radiation units for different applications.

In one embodiment of the invention at least one radiation unit comprises a light guide for guiding at least a part of said optical radiation. A light source, such as an LED, emits light in many directions. A light guide may collect some of this light and direct it in a certain direction.

In one embodiment of the invention at least one radiation unit is adapted to be attached to the skin of the user at said extra-cranial position. The known device by the same applicant directed the light to the brain via the external auditory canal. However, as previously stated the light can penetrate the skull and thus the auditory canal does not have to be used. It may be preferential to be able to attach the radiation unit(s) anywhere on the head of the user, e.g. by providing some sticky material or other attaching means to each radiation unit. In particular at least one radiation unit may be adapted to be arranged such that at least part of said optical radiation is guided trans-cranially through the at least one of the followings cranial bones: the temporal bone, squama temporalis of the temporal bone, mastoid portion of the temporal bone, petrous portion of the temporal bone, tympanic part of the temporal bone, the zygomatic bone, the sphenoid bone, the frontal bone, the parietal bone.

In another embodiment of the invention at least one radiation unit is adapted to be arranged at an external ear of the user, e.g. by using the ear as attachment “peg”. The earlobe may also be used, i.e. a radiation unit may be adapted to be arranged on or via an earlobe of the user.

As known from the prior art device at least one radiation unit may be adapted to be arranged at least partly inside an external auditory canal of the user. At least one radiation unit may be adapted to be arranged such that at least part of said optical radiation is guided into an external auditory canal of the user.

In a further embodiment of the invention the radiation units may be arranged via a headband structure accommodating the radiation unit(s).

In one embodiment of the invention the extra-cranial position is selected from the group of: the external auditory canal, behind the pinna, behind the earlobe, at Reid's base line, the temporal bone, squama temporalis of the temporal bone, mastoid portion of the temporal bone, petrous portion of the temporal bone, tympanic part of the temporal bone, the zygomatic bone, the sphenoid bone, the frontal bone.

In one embodiment of the invention said one or more neuroanatomical brain structures are selected from the group of: the brain stem, medulla oblongata, pons, midbrain, substantia nigra, raphe nuclei, nucleus raphe obscurus, raphe magnus, raphe pontis, raphe pallidus, nucleus centralis superior, nucleus raphe dorsalis, nuclei linearis intermedius and linearis rostralis.

The inventors have observed opsins (OPN3, OPN4 and most recently, rhodopsin) all over the brains. They are abundant at least in:

-   -   frontal cortex     -   temporal lobes     -   cingular cortex     -   parietal lobe     -   postcentral area and prae     -   occipital lobe     -   hippovampus     -   hypothalamus     -   striatum     -   thalamus     -   mesencephalon including substantia nigra     -   pons incl. raphe nucleus     -   medulla     -   cerebellum (vermis)     -   cerebellar cortex     -   medulla spinalis     -   Pituitary gland     -   pineal gland         in addition also testis are photosensitive to at least via OPN3         & OPN4

The amount of possible diseases and symptoms via these regions is huge, including all major mood diseases, neurological, hormonal, cognitive, motor performance, memory & learning, language, skill or any brain related disease/symptom. Also, the wide variety of different wavelengths seem to have an array of responses due to different concentrations of each opsin in different brain areas.

As previously stated a further aspect of the invention relates to a medical device comprising radiation means for directing light via the ear canal of a subject for use in light therapy comprising non-invasive intra-cranial administration of bright light using a luminous flux of 0.7-12 lumens for 1-15 minutes.

The invention primarily provides a dose and secondarily a schedule of intra-cranial administration of bright-light direct-to-brain via the ear canal. The subject to be treated is a mammalian, preferably a human being. The bright light is directed non-invasively at the brain tissue through an external auditory canal of the subject to stimulate the subject's brain tissue. Preferably the light is directed via both ear canals. The ear canal enables accurate administration of bright light to induce the intended therapeutic effect without adverse events as the amount of light exposure is highly controlled.

The bright light treatment is conducted using a medical device comprising radiation means for administering the light non-invasively to the brain tissue via the external auditory canal of the subject to be treated. The medical device may be a portable electronic device, wherein the radiation means comprise an optical radiation source for generating optical radiation, and a light guide for guiding optical radiation from the optical radiation source into the external auditory canal. Optical radiation can be directed by means of a plurality of light units such as leds. The device may further comprise adapter means for arranging the radiation means in the user's external ear to enable ease-of-use and accurate administration of light via the ear canal. According to one embodiment, the radiation means and the adapter means form an earpiece to be placed on an earlobe. The adapter means are conveniently arranged so that they at least partly penetrate into the external auditory canal. The device may further comprise a controller to adjust bright light administration and optical radiation, for example intensity, time, spectrum and spatial distribution in the brain. One such device is described in WO 2008/029001, which is incorporated herein by reference. Other devices may also be used.

The quality of the light delivered affects the spatial distribution of the light in the brain. According to one embodiment of the invention an intensity of 0.7-12 lumens, typically 1-10 lumens, is used. In most cases 3-9 lumens is safe and sufficient for obtaining a clinical effect without adverse effects. In one embodiment an intensity of 4-9, or 6-9 lumens is used. With a light intensity of 1-12 lumens treatment times of 1-15 minutes, in most cases 6-12 minutes are suitable and adequate, e.g. 8-12 minutes treatment times are well applicable. In one embodiment of the invention the optimal optical radiation dose i.e. the light dose is 3-9 lumens for 6-12 minutes. According to one embodiment the light dose is 6-9 lumens for 8-12 minutes. A higher light intensity typically requires a shorter illumination time and vice versa.

In one embodiment of the invention bright light is used, which here refers to optical radiation that ranges in the visible spectrum from about 380 nm to about 780 nm, or in adjacent radiation regions of infrared and ultraviolet, which are not visible to the human eye. Typically the light is visible light, and especially light imitating natural sunlight. Illumination via the ear canal with light having a primary light spectrum peak in the blue region i.e. between 450 and 475 nm and a secondary in the green region i.e. between 495 and 570 nm can be very effective. The therapeutic effect can be induced by such a spectral power distribution as a whole, or its spectral power peaks, for example the 1.5 E-04 W/nm peak at approximately 465 nm or 1.0 E-04 W/nm peak at approximately 550 nm. The wavelength distribution of optical radiation typically changes due to absorption in tissue.

Serotonin

The inventors have realized that non-invasive application of trans-cranial light therapy may trigger the production, release, re-uptake, metabolism and dynamics of serotonin in various part of the human brain. Additionally, serotonin stored in platelets might be released from platelets, especially with certain wavelengths. One object of the invention is therefore to provide a device that enables the control of the natural production, release, re-uptake and/or metabolism of serotonin in humans. Thus, a further aspect of the invention therefore relates to a novel application of the device, i.e. a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in altering and/or controlling (natural) production, release, re-uptake and/or metabolism of serotonin in at least one of said one or more neuroanatomical brain structures and/or in the body of the user. In particular the inventors have realized that the serotonin level in raphe nuclei may be influenced by trans-cranially applied light.

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. It is a well-known contributor to feelings of well-being; it is also known to contribute to happiness. Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons in the CNS where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Recent studies involving the serotonin transporter gene 5-HTT have shown the short allele of this gene increases synaptic serotonin levels. These genetic studies have demonstrated serotonin has strong associations with depression in regards to a negative environment. Increased level of serotonin is thought to decrease appetite.

Locus coeruleus seems to be the main site for serotonin production whereas the neurons of the raphe nuclei are the principal source of serotonin release in the brain. The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.

The most prescribed drugs in many parts of the world are drugs which somehow alter the serotonin level. But serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and does cross the blood-brain barrier. These agents are available as dietary supplements, and may be effective serotonergic agents. Examples of other serotonin relates drugs are Monoamine oxidase inhibitors (MAOI), which prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain, and selective serotonin reuptake inhibitors (SSRI or SRI) which stimulate serotonin reuptake in the body.

However, there is virtually no pharmaceutical treatment known that does not, apart from its benefits to patients, also carry some degree of risk of adverse side effects. 5-HTP monotherapy has been associated with gastrointestinal (nausea, vomiting, diarrhea) and psychopathological (acute anxiety state, hypomania) side effects in open studies with human patients. One approach to managing these risks of side effects may be to lower the dose of 5-HTP. With respect to SRIs, possible side effects to be balanced against the known benefits of SRIs and to be managed may include sexual dysfunction and sleep disturbances. Many patients experience delayed onset of a therapeutic effect during SRI monotherapy. Further clinical studies on depression and anxiety disorders indicate that more than 30% of patients treated with SRI monotherapy as a class are non-responsive.

All pharmaceutical treatments are therefore effectively detours towards the final goal of controlling the level and production of serotonin, because serotonin does not cross the blood-brain barrier. With the present invention the principal and natural source of serotonin production can be targeted directly. This opens for a range of applications for a device delivering optical radiation trans-cranially. Thus, as a further embodiment of the invention relates to a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures, such as raphe nuclei, of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in treatment of anxiety, migraine, depression, obesity and social phobia.

The serotonin system is very complex with at least 17 different serotonin-receptors and pathways. Pharmaceutical therapy is a brute force method that is not fine-tuned to this complex system and may result in overshooting of some parts of the system which may lead to the known undesired effects of pharmacotherapy. Therefore, the inventors regard light-induced serotonin release to be physiologically correct way, also in terms of the role of serotonin during day-time with illumination rhythmicity. The light induced serotonin control is a tuned concert where desired “sub-pathways” of the serotonin system are functioning optimally relative to each other. Also, light-induced allostery of EAA-receptors is involved in this, making serotonin pathways work optimally when excretion and other dynamics of action are induced photically.

A further embodiment of the invention relates to a method for treatment of a disorder comprising the step of non-invasively applying a physical stimulus in the form of optical radiation to a neuro-anatomical brain structure, such as raphe nuclei, wherein the physical stimulus is sufficient for inducing a change in the level, such as an increase in the level, of serotonin in said neuro-anatomical brain structure, wherein said disorder is selected from the group of anxiety, depression, delirium, Alzheimer's disease, ADHD, infertility, migraine, seasonal affective disorder (SAD), cancer, obesity, circadian rhythm sleep disorders, jet lag, shift work disorder, Parkinson's disease, burning mouth syndrome, fibromyalgia, restless legs syndrome, social anxiety, hypertension (HTN), cognitive impairment, migraine, headache, social phobia, Generalized anxiety disorder (GAD), chronic pain and/or decreased cognitive performance.

Based on experiments conducted by the inventors it has been surprising to find that raphe nuclei contains light sensitive opsin (at least OPX3 and melanopsin/OPX4). Based on measurements the OPX has light absorption maximum at wavelengths which are illustrated in FIG. 2. Further Neuropsin is recently shown to absorb light at least in the UV-wavelength range, i.e. the leftmost curve in FIG. 2. Neoropsin/OPN5 is bistable chemically having actually two absorption peaks at 360 nm and 474 nm.

These opsins are therefore sensitive to light with wavelengths corresponding preferably to their absorption maximum. It appears based on the conducted studies that trans-cranial stimulation of the raphe nuclei with optical radiation in the form of light affects opsins with the result that production of serotonin is affected, e.g. an increase and/or optimization of action of the production of serotonin. Additionally light might influence various mechanisms related to the amount of serotonin stored in vesicles or in platelets in the blood. The raphe nuclei part of the brain can therefore be stimulated with light non-invasively and without the use of pharmaceuticals by means of the device according to the invention, e.g. light provided trans-cranially below the cerebrum, e.g. via the auditory canal using for example LED lights, preferably light with the same wavelengths as absorption of OPX's found in raphe nuclei. The flow chart below illustrates an exemplary procedure:

Raphe nuclei not producing sufficiently serotonin→Illuminating raphe nuclei with light→Stimulating OPX5, OPX3 . . . →Accelerated production of serotonin→Distribution of the correct relative amounts of serotonin to different parts of the brain.

Affecting the serotonin system using light therapy has a potential effect to any known disease/disorder/symptoms having aetiology or underlying mechanisms relating to the serotonin system. More and more are found, but to date known are at least:

-   -   depression(s)     -   anxiety     -   Generalized anxiety disorder (GAD)     -   SAD     -   chronic pain     -   migraine     -   decreased cognitive performance

Dopamine

The inventors have realized that the non-invasive application of trans-cranial light therapy may trigger the production of dopamine in various parts of the human brain. Thus, a further aspect of the invention relates to a novel application of the device, i.e. a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures, such as substantia nigra, of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in altering the level of dopamine in at least one of said one or more neuroanatomical brain structures. In particular the inventors have realized that the dopamine level (produced) in substantia nigra, substantia nigra pars compacta and the ventral tegmental area may be influenced by trans-cranially applied light. Substantia nigra seems to be the main site for dopamine production and may be thought of as the grand central railway station for dopaminergic pathways.

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors: D1, D2, D3, D4, and D5 and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area. Dopamine has many functions in the brain, including important roles in behavior and cognition, voluntary movement, motivation, punishment and reward, inhibition of prolactin production (involved in lactation and sexual gratification), sleep, mood, attention, working memory, and learning.

Dopamine is available as intravenous medication acting on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, because dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson's disease and dopa-responsive dystonia, L-DOPA (the precursor of dopamine) is often given because it crosses the blood-brain barrier relatively easily.

With the present invention the principal source of dopamine production can be targeted directly. This opens for a range of applications for a device delivering optical radiation trans-cranially. Thus, a further embodiment of the invention relates to a device for non-invasive/trans-cranial light therapy comprising one or more radiation units adapted to direct optical radiation at one or more neuroanatomical brain structures, such as substantia nigra, of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in treatment of Parkinson's disease, burning mouth syndrome, fibromyalgia, restless legs syndrome, social anxiety, ADHD and/or hypertension (HTN). The device may further be applied for use in pain processing in multiple levels of the central nervous system.

A further embodiment of the invention relates to a method for treatment of a disorder comprising the step of non-invasively applying a physical stimulus in the form of optical radiation to a neuro-anatomical brain structure, such as substantia nigra, wherein the physical stimulus is sufficient for inducing a change in the level, such as an increase in the level, of dopamine in said neuro-anatomical brain structure, wherein said disorder is selected from the group of Parkinson's disease and hypertension (HTN). Also, light-induced allostery of EAA-receptors is involved in this, making the dopamine pathways work optimally when excretion and other dynamics of action are induced photically.

Affecting the dopamine system using light therapy has a potential effect to any known disease/disorder/symptoms having aetiology or underlying mechanisms relating to the dopamine system. More and more are found, but to date known are at least:

-   -   Parkinsons     -   anxiety     -   depression     -   cognitive impairment

Treatment

The present invention provides the means and methods for the prevention, treatment and/or amelioration of diseases and/or disorders which are related to chemical imbalances of the body, in particular chemical imbalances in the brain and in particular the human brain. The method comprises providing physical stimulus to the brain of a user in need of treatment, thereby inducing changes in the level and/or the production of one or more chemical compounds in the brain.

The present invention especially provides a treatment alternative for a cluster of central nervous system (CNS) conditions, mood disorders, circadian rhythm sleep disorders and inflammatory diseases. CNS conditions as used herein and responsive to light therapy include but are not limited to: seasonal affective disorder (SAD), major depressive disorder (MDD), bipolar affective disorder, obsession compulsive disorder (OCD), migraine, post-traumatic stress, postpartum depression. Alzheimer's disease, Parkinson's disease, and anxiety. Circadian rhythm sleep disorder includes but is not limited to jetlag, shift work sleep disorder, and insomnia. Inflammatory diseases include but are not limited to autoimmune diseases like psoriasis, atopic skin, and skin disorders. Further premenstrual syndrome (PMS), and fertility disorders can be treated with light therapy.

The effect of the light therapy described may be monitored by analyzing resting-state functional connectivity of the human brain. Spatial domain independent component analysis (ICA) may be applied to resting-state functional magnetic resonance imaging (fMRI) data in order to identify changes within the resting state networks (RSNs) that cover the entire cerebral cortex of the test persons. The entire brain cortex may be functionally segmented into a plurality of RSNs. Statistically significant increases in the functional brain connectivity of affected RSNs indicate the response to the light treatment. Changes in magnetic susceptibility correspond with changes in blood-oxygen-level (BOLD) contrasts in the region.

The processes that occur in the brain during radiation with light have not been completely outlined. It is known that opsins mediate phototransduction in both visual and non-visual systems by being trans-membrane proteins acting as G-protein-coupled receptors (GPCRs). Until now, several studies, per se, show that genes of extra-visual opsins are also expressed in mammalian brain in the mRNA-level. Furthermore, there is now initial evidence that e.g. encephalopsin, also termed OPN3 or panopsin exists in the protein level in the human brain. Panopsin protein expression has recently been observed in substantia nigra neurons by White et al. (“Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation. Human Molecular Genetics, 17, 1890-1903 (2008)). OPN3 has been suggested to play a role in non-visual photic processes such as the entrainment of circadian rhythm or the regulation of pineal melatonin production even though the exact function of encephalopsin is largely unknown. However, the role of OPN3 is most likely related into its phylogenetic background as an extra-retinal ciliary phototransductive membrane protein, e.g. by means on ciliary structure. OPN3 may also affect neuro regenerator and stem cell differentiation into neural and/or glial cells in the brain. OPN3 may also affect immune response and inflammation in the brain.

With the present invention it has been realized that endogenous opsins maintain their functional role as a part of extra-visual phototransduction. Consequently it is has been realized by the inventors that light therapy does not have to be mediated through the eyes.

It is an object of the present invention to target specific opsins in specific neuro-anatomical regions of the brain by means of non-invasive trans-cranially applied optical radiation. It is a further object of the present invention to thereby alter the amount, level and/or production of one or more hormones, neuro-transmitters or other chemical compound in said neuro-anatomical brain region, and thereby correct chemical imbalances in the body and/or brain which may be the cause of a disorder.

Method

The present application thus provides a method of prevention, treatment and/or amelioration of a disease and/or disorder which is related to a chemical imbalance in the body, the method comprising the comprising the step of applying a physical stimulus to a neuro-anatomical brain structure, wherein the physical stimulus is sufficient for inducing a change in the level, such as an increase or decrease in the level, of at least one chemical compound in said neuro-anatomical brain structure.

In the preferred embodiment of the invention the physical stimulus is applied non-invasively. And preferably the physical stimulus is applied from an extra-cranial position, preferably below the cerebrum.

In the preferred embodiment of the invention the physical stimulus is applied with a predefined setting. The physical stimulus is preferably optical radiation, such as visible light. UV light or infrared light. The spectral composition of the physical stimulus may be adapted to the absorption spectrum of one or more light sensitive opsins.

In the preferred embodiment of the invention the physical stimulus is optical radiation with one or more of the following parameters being predefined: duration, intensity, total power and spectral composition.

In the preferred embodiment of the invention the physical stimulus is optical radiation with one or more of the following parameters being predefined for a plurality of predefined wavelength intervals: duration, intensity, total power, spectral output and spectral composition.

In the preferred embodiment of the invention the physical stimulus is optical radiation wherein the ratio of:

a first spectral output integrated over a first wavelength interval, and a second spectral output integrated over a second wavelength interval, is predefined.

In a further embodiment of the invention the physical stimulus is optical radiation wherein the ratios of:

a first spectral output integrated over a first wavelength interval, a second spectral output integrated over a second wavelength interval, and a third spectral output integrated over a third wavelength interval, are predefined.

The extra-cranial position may be selected from the group of: the external auditory canal, behind the pinna, behind the earlobe, at Reid's base line, the temporal bone, squama temporalis of the temporal bone, mastoid portion of the temporal bone, petrous portion of the temporal bone, tympanic part of the temporal bone, the zygomatic bone, the sphenoid bone, the frontal bone.

The neuro-anatomical brain structure may be selected from the group of: the brain stem, medulla oblongata, pons, midbrain, substantia nigra, raphe nuclei, nucleus raphe obscurus, raphe magnus, raphe pontis, raphe pallidus, nucleus centralis superior, nucleus raphe dorsalis, nuclei linearis intermedius and linearis rostralis, frontal cortex, temporal lobes, cingular cortex, parietal lobe, postcentral area and prae, occipital lobe, hippovampus, hypothalamus, striatum, thalamus, mesencephalon including substantia nigra, pons incl. raphe nucleus, medulla, cerebellum (vermis), cerebellar cortex, medulla spinalis, Pituitary gland and pineal gland.

The chemical compound may be selected from the group of endogenous chemicals, hormones, adrenalin, neurotransmitters, monoamines, norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline) and histamine.

The disorder may be a psychological disorder selected from the group of: anxiety, depression, delirium, Alzheimer's disease, ADHD, infertility, migraine, seasonal affective disorder (SAD), cancer, obesity, circadian rhythm sleep disorders, jet lag, shift work disorder, Parkinson's disease, burning mouth syndrome, fibromyalgia, restless legs syndrome, social anxiety, hypertension (HTN), cognitive impairment, migraine, headache, social phobia, Generalized anxiety disorder (GAD), chronic pain and decreased cognitive performance.

The device may further be applied for use in pain processing in multiple levels of the central nervous system.

In the preferred embodiment of the invention the physical stimulus is applied by means of the device as described herein.

The light therapy can be conducted by providing the medical device described, applying the device to a subject in need of such therapy, and directing optical radiation with a luminous flux of 0.7-12 lumens, typically 3-9 lumens non-invasively to the brain of the subject through an external auditory canal of the subject for 1-15, typically 6-12 minutes to stimulate the brain tissue of the subject.

Light therapy treatment, using the light intensity and illumination times disclosed in the present invention, once a day may in some cases be sufficient to achieve a clinical effect. This once-a-day treatment may be conducted for 1-3 or 1-5 days, or 1-4 or 1-6 weeks, or 1-3 or 1-6 months, or longer, or whenever needed depending on the disorder to be treated. Several daily doses, usually up to three daily doses, may be applied to treating an active migraine attack, fertility disorders, autoimmune diseases, Parkinson's disease, Alzheimer's disease, bipolar affective disease, OCD, or postpartum depression. Low light intensity, starting from 1 lumen may be used in treatments that continue for several weeks and/or for maintenance of a healthy condition.

Individual to be Treated

The “user” of the device according to the present invention may be any animal or human being. The method is generally practiced on the head of an animal or a human being. Preferably the individual to be treated is a mammal, such as but not limited to a dog, cat, primate, horse, cow or human being.

DETAILED DESCRIPTION OF DRAWINGS

Pharmaceutical drugs are distributed to the body via the blood system. It is therefore likely that the drug will be distributed wherever the blood system reaches. It is further likely that this will cause a substantially equal increase of the “base level” concentration of the compound/hormone/neurotransmitter in the body. Adverse side effect of pharmaceuticals might arise due to this general increase in base level that might cause an imbalance compared to the natural concentration distribution of the compound/hormone/neurotransmitter. With the present device the natural production of the compound/hormone/neurotransmitter is targeted thereby maintaining the natural distribution channels that will lead to a correct distribution to target areas.

FIG. 1 a is a cross-sectional side view illustration of the human brain. The neuro-anatomical structures caudal raphe nuclei and rostral raphe nuclei are both part of raphe nuclei located in the brain stem. Raphe nuclei is a source of serotonin production in the brain and the arrow shows the natural distribution pathways of serotonin produced in caudal raphe nuclei and rostral raphe nuclei, respectively.

FIG. 1 b is a cross-sectional schematic diagram of the human brain schematically illustrating specific neuro-anatomical regions and the serotonin pathways originating from raphe nuclei. The orientation of the brain in FIG. 1 b is reversed around a vertical axis compared to FIG. 1 a, e.g. cerebellum is in the left side of FIG. 1 a and in the right side of FIG. 1 b.

FIG. 4 is a cross-sectional side view illustration of the human brain. Substantia nigra and VTA are sources of dopamine production in the brain and the arrows show the natural distribution pathways of dopamine produced in substantia nigra and VTA, respectively. It is seen from the figure that substantia nigra provides dopamine to the striatum whereas VTA provides dopamine to the hippocampus, nucleus accumbens and the frontal cortex.

FIG. 8 a shows an example of the wavelength spectrum of a phosphor based white LED. These LEDs are provided by coating an LED of one color (mostly blue LED made of InGaN) with phosphor of different colors to form white light. Depending on the color of the original LED, phosphors of different colors can be employed. If several phosphor layers of distinct colors are applied, the emitted spectrum is broadened, effectively raising the color rendering index (CRI) value of a given LED. The X-axis of the graph in FIG. 8 a is the wavelength of the light in nanometers (nm) and the Y-axis is the spectral power in Watt/nm. In the graph the LED emits light with maximum power at two peaks of about 450 nm and about 560 nm.

FIG. 8 b shows example of how to calculate the spectral output emitted between certain wavelengths. The underlying spectrum is the same as in FIG. 8 a. Integrating from 425 nm to 475 nm results in a total power of about P₄₂₅₋₄₇₅=3.9 mW (the area indicated with 20 in the figure), integrating from 570 to 620 nm results in a total power of about P₅₇₀₋₆₂₀=4.5 mW (indicated with 22 in the figure), and integrating from 700 nm to 750 nm results in a total power of P₇₀₀₋₇₅₀=0.37 mW of power.

Based on clinical trials it appears that both relative proportion of total power and/or energy of two or more frequency areas are important on medical impact to patient. I.e. ratios such as P₄₂₅₋₄₇₅/P₇₀₀₋₇₅₀ and/or P₇₀₀₋₇₅₀/P₅₇₀₋₆₂₀ or applied energy ratio such as t₁×P₇₀₀₋₇₅₀/t₂×P₅₇₀₋₆₂₀ where t₁ and t₂ correspond to the time each power in each wavelength interval has been applied. Wavelength intervals might also overlap for example P₄₀₀₋₅₀₀/P₄₅₀₋₆₀₀

Based on research conducted by the inventors different neuro-anatomical regions of the brain have different presence, concentration and/or amount of light sensitive opsins (opsin 1, 2, 3 etc.). Each opsin typically has a characteristic absorption spectrum, i.e. most of the absorption of light happens in certain wavelengths as shown in FIG. 2. The nature (e.g. the spectral composition) of the optical radiation therefore influences which type of substance(s) that is produced (e.g neuro transmitters, hormones etc.) or which chemical balance that is triggered. One embodiment of the invention therefore relates to the balance/ratio between energies in different wavelength intervals and the different medical impacts that results from this. Additionally there might be neural synapses with no opsins, which are activated by light.

Further, some opsins, such as neuropsin OPN5, might have bistable forms and therefore two or more absorption peaks. Furthermore, changes in gene reading can produce variants of the same protein; being close enough and functionally adequate, this mechanism may also produce opsin-variants of the same gene with other absorption peaks.

The basic process can then essentially be that a) light of a certain wavelength, b) creates a response in the brain, c) this will change neural transmission characteristics, d) this can lead to production of for example hormones or neural transmitters, e) said hormones or neural transmitters affect patients.

For example if the ratio of spectral output from different wavelength intervals tends towards shorter wavelengths, the production of a first neuro-transmitter/hormone is lower than the production of a second neuro-transmitter/hormone. On the other hand: if relative amount of energy coming from longer wavelength is higher than the amount of energy coming from shorter wavelengths, the relative production of the second neuro-transmitter/hormone might be lower than relative production of the first neuro-transmitter/hormone, i.e. the resulting chemical balance is influenced by the nature of the light.

The present invention is not limited to the use of two or more LEDs. The radiation units of a light therapy device according to the invention can be provided with a single LED with known fixed spectrum where this fixed spectrum is known to affect specific symptoms of one or more disorders. For example the spectrum of a “Blue color white LED” has a different spectrum than a “Red color white LED”

An example of creating different spectral power functions using several LEDs is shown in FIG. 8 c. In the example there are four LED's 30, 34, 36, 38, each with a characteristic wavelength spectrum. 36 is a white LED, 34 has a main peak at 490 nm, 30 has a main peak at 520 nm, 38 has a main peak at 730 nm. In case all LED's are ON at the same time a possible effective output spectrum 32 is created (the graph has been offset in the figure for clarity purposes).

If the power supplied to each of the four LEDs can be controlled independently, the power and energy of the peaks in the output spectrum 32 can be adjusted. As an example if 38 is shut down the amount of energy and power in near infrared area will be much lower than in case of having it on

In general terms the device according to the present invention could have an arbitrary amount of light sources, such as LED's, each emitting light with a characteristic and known spectrum. Modification of the output power and the time the power is applied can alter the combined spectral output and thereby the effect on light therapy treatments can be altered.

FIG. 9 shows an example of a (part) of a radiation unit with four LED's (Light Emitting Diodes) 44 installed in a printed circuit board 40. The LED's can have also one or more phosphorous layers 46 on top of them. LED output power and timing can be controlled for example with a Digital Signal Processor (DSP) 42.

The light emitting device according to the invention can also have other form factors, such a lamp to be placed in the table or on the ceiling.

In order to control which applied energies in different wavelength intervals the device according to the invention can have a user interface for adjusting output power/energy levels/ratios in certain wavelength intervals. The light emitting device might further have a user interface to select which medical condition the light therapeutic treatment should apply.

The light emitting device might further have an interface to connect to an external device such as laptop to make modifications to the energy levels, wavelength intervals and/or ratio of spectral outputs. The device might further have an interface to connect to the Internet (directly or via PC (Personal Computer)/laptop or smart phone) to download new programs/energy level form factors or light therapy programs.

FIG. 10 shows a high level architecture. The light therapy device 50 according to one embodiment of the invention can be connected via a personal computer 54 to server system 58 via Internet 52. The device 50 can be connected to PC 54 wirelessly using for example Bluetooth™ or WLAN (Wi-Fi) connectivity. The device 50 can be connected to pc 54 with wire such as Universal Serial Bus (USB) connectivity. The device 50 can be also connected directly to server system 58 via Internet 52 in case the device has connection means such as WLAN (Wireless Local Area Network) or for example integrated cellular modem. The device can be also be connected to Internet for example via Smart Phone or mobile phone. The device can be part of a mobile phone/smart phone or it can be accessory to a mobile phone/smart phone.

The server system 58 contains set of servers 582 either located centrally or distributed in as cloud service. Server can be for example run on Apache™. Server system 58 can include database 584 such as MySQL or other relational or non-relational database. The purpose of the server system is to store settings related to light therapy devices 50. The server system can also host patient related data such as gender, age, symptoms, applied light therapies, results of the therapies. The system can host plurality of different type of light therapy programs for varying applied energy and timing for each feasible light wavelength range.

Based on embodiments of the invention there can be at least following high level type of light therapy programs

1) General programs which are feasible for most of the patient. These programs are typically programmed by doctors or other medical persons. 2) Customized programs based on patient responses to treatments. These programs can be programmed also by medical persons, but there might be feedback loop and possibility for patients to modify these programs. Programs can be programmed by patients using web interface and laptop 54. Persons can be for example provide information of used medicines and other illnesses.

The web interface is useful also in collecting possible side effect information.

3) Light therapy programs created/modified by users of and shared to other users. The sharing can take place by users uploading their experienced best practices to server system 58 via PC 54 or 56 over web interface. In addition users of personal computers (or smart phones etc.) can share in some embodiments the programs and feedback on programs via 3^(rd) party service 55 such as Facebook™ or other social networking platform.

FIG. 11 shows three different wavelength spectrums 70, 72, 74 of optical radiation, each having two intensity peaks but with different ratios of spectral outputs integrated around each peak. Each spectrum may have a different effect when applied trans-cranially into the brain. The three spectrums can e.g. be provided by a multi LED device.

Example 1

As an example the amount and ratio of blue and red light might be an important factor for treatment of SAD, anxiety, migraine and/or urinary incontinence. FIGS. 15A-15E show various spectral compositions of LED's of certain types that has been tested for treatment purposes.

FIG. 15A shows examples of measurement of the spectral power (Watt/nanometer) of two type “A” LED's used to treat patients. Type A spectra have been found in a number of conducted experiments to be efficient on curing SAD related symptoms. From the graph it can be seen that the blue peak wavelength is at approx. 450 nm with a half peak width of about 30 nm. The peak starts from about 410 nm and reaches to about 480 nm. The “red” peak maximum value is lower with the peak power wavelength at about 566 nm. Peak starts from about 500 nm and goes up to 630 nm. There is small additional peak at 644 nm. Additionally it has been found out that a LED spectrum resembling the spectrum in FIG. 15A has been efficient on curing urinary incontinence. In some experiments type “A” has been found to cause side effects such as headache or migraine. The spectral output from 380 nm to 480 nm (blue peak) is 13.2 mW and 9 mW, respectively, for the two spectra (found by integrating the spectral power from 380 to 480 nm). The spectral output from 481 to 780 nm (red peak) is 21.2 and 16.1 mW, respectively, for the two spectra (found by integrating the spectral power from 481 to 780 nm). The total power is thus 34.4 mW and 25.1 mW, respectively. The ratio between the blue and red light of the two LEDs is thus 13.2/21.2=0.62 and 9/16.1=0.56, respectively.

FIG. 15B shows examples of measurements of the spectral power (Watt/nanometer) of five type “B” LED's used to treat patients. Type B spectra have been found in a number of conducted experiments to be efficient on curing SAD related symptoms. From the graph it can be seen that the blue peak wavelength is at approx. 448 nm with a half peak width of about 30 nm. The peak starts from about 418 nm and reaches to about 480 nm. There is some “red” light with the peak at 562 nm. Additionally it has been found that Type B spectra have been efficient on curing urinary incontinence. For some patient type B spectra have been found to help on, e.g. reduce symptoms of, anxiety and migraine. The spectral output from 380 nm to 480 nm (blue peak) is between 6.1-7.8 mW for the five spectra. The spectral output from 481 to 780 nm (red peak) is between 8.5 and 10.9 mW for the five spectra. The total power is thus between 14.6 and 18.8 mW. The ratio between the blue and red light of the five type B LEDs are between 0.678 and 0.719.

FIG. 15AC shows examples of measurement of the spectral power (Watt/nanometer) of two type “C” LED's used to treat patients. Type C spectra have been found in a number of conducted experiments to be efficient on curing SAD related symptoms. From the graph it can be seen that the blue peak wavelength is at approx. 450 nm with a half peak width of about 30 nm. The peak starts from about 420 nm and reaches to about 480 nm. There is a “red” light peak with the peak maximum at 562 nm. Additionally it has been found that type C spectra have been efficient on curing urinary incontinence. Additionally it has been found in conducted experiments that type C spectra can treat symptoms of anxiety and migraine. The spectral output from 380 nm to 480 nm (blue peak) is 3 mW and 4.1 mW, respectively, for the two spectra. The spectral output from 481 to 780 nm (red peak) is 9.4 mW and 13.5 mW, respectively, for the two spectra. The total power is thus 12.4 mW and 17.6 mW, respectively. The ratio between the blue and red light of the two LEDs is thus 0.323 and 0.308, respectively.

FIG. 15D shows examples of measurements of the spectral power (Watt/nanometer) of four type “D” LED's used to treat patients. Type D spectra have been found in a number of conducted experiments to be efficient on curing SAD related symptoms, however impact has not been as good as with LED types “A”, “B” or “C”. In addition type “D” has been found to cause side effect such as headache. From the graph it can be seen that the blue peak wavelength is at approx. 450 nm with a half peak width of about 30 nm. The peak starts from about 420 nm and reaches to about 480 nm. There is a “red” light peak with the peak maximum at 562 nm. The spectral output from 380 nm to 480 nm (blue peak) is between 2.5-3.2 mW for the five spectra. The spectral output from 481 to 780 nm (red peak) is between 12.2 and 15.2 mW for the five spectra. The total power is thus between 14.7 and 18.3 mW. The ratio between the blue and red light of the five type B LEDs are between 0.208 and 0.22.

FIG. 15E shows examples of measurements of the spectral power (Watt/nanometer) of a set of type “E” LED's used to treat patients. Type E spectra have been found in a number of conducted experiments to be efficient on curing SAD related symptoms. A spectrum 15E1 (dashed line, marked in figure) has been found to have an effect on anxiety and migraine. The ratio between blue peak integral to red peak integral for 15E1 is 0.56. Additionally it has been found that variation in manufacturing technologies used to produce LED's can lead to variation in the wavelength location of the maximum of the blue peak between 430-480 nm.

Additionally some patients have been exposed to “pure” blue, i.e. a spectrum having little or no red peaks (ratio>>1). Said spectrum has been found to cause side effects such as migraine to patients.

Summary of Studies

Treatment of SAD and/or urinary incontinence

-   -   The treatment should be conducted with LED spectrum which is at         or below type “A” spectrum preferably close to type “B”.     -   The spectrum preferably has sufficient amount of “blue” color,         i.e. higher than in type “D”.     -   In order to avoid non desired side effects the blue color peak         maximum should be higher than red color peak maximum.     -   Additionally it has been found that when the total power is too         high or when red color peak power is too high there might be         side effects relating to headache or migraine.     -   Preferably, in order to avoid side effects the ratio between         blue and red peaks should be higher than 0.25.     -   Additionally the total power should be under 34 mW to avoid side         effects (for used treatment times, i.e. to derive total energy).     -   Preferably the spectrum should not be mostly blue.         Treatment of Migraine and/or Anxiety     -   Spectra types “B”, “C” and 15E1 have been found useful, however         the spectrum should preferably be type “B” or below.     -   Peak power of the red peak should preferably not significantly         exceed 0.1 mW/nm since higher red powers have been found to         cause migraine in some patients. Preferably the ratio between         integrals of blue peak vs red peak should be between 0.3 and         0.9.     -   The total power should not be too high (preferably below 34 mW         per ear) since it has been found to cause migraine as side         effect.

In typical treatments timing used has been varying between 6-12 minutes. Treatment has been applied to both ears at the same time resulting in a total maximum energy of (in case of type “A”) 2×12 min×60 sec/min×34 mW=50 Joules and with minimum energy of 2×6 min×60 sec/min×15.7 mW=11 Joules.

Example 2

A study is being conducted to measure the acute effect of trans-cranial illumination on mouse brains. The aim of the study is further to measure the neuro endocrinological responses in the mouse brains.

A plurality of mice is randomized into two groups; one group is receiving trans-cranial light therapy via the auditory canals for eight minutes by means of device according to the present invention. A second group is wearing the light therapy device, however without receiving illumination from the device.

All mice are executed by cervical dislocation immediately after light therapy. Subsequently blood samples from cranial circulation and tissue samples from various neuro anatomical brain structures, PVA, Mesencephalon, Cerebral cortex, Medulla oblongata and Hippocampus are collected.

By analyzing the blood and tissue samples the amount of a number of hormones and neurotransmitters, such as dopamine, in the various neuro-anatomical brain structures can be determined. And by comparing the results from the two groups of mice, and testing for statistical significance, the acute effect of trans-cranial light therapy in mice can be determined, i.e. it can be directly confirmed that trans-cranial light therapy directed non-invasively from an extra-cranial position of a test subject results in altering of the amount, level, production, release, re-uptake and/or metabolism of dopamine in the brain of the test subject.

Example 3

The patient (male, 70 years old) had been diagnosed with Parkinson's disease. Light therapy was applied to the patient using the device according to the invention. The light spectrum 15E1 as shown in the Figure 15E1 was applied through the ears of the patient for 12 minutes daily. During the treatment of two weeks the patient reported significant improvement, i.e. a significant reduction in symptoms related to Parkinson's. In the first phase (during first days of use) anxiety related to Parkinson's remitted. During the following weeks motor performance and cognitive speed was observed to improve and motor performance (tremor was decreased) and overall movement speed increased. Also the observer (the patient's adult son) noticed improved speech rate, increased speed of thinking and improved mood.

The patient himself reported immediate anxiolytic effect of the light therapy, and experienced that eased anxiety was related to Parkinson's also. The patient reported overall increased quality of life and was able to perform daily tasks on days when light was administered. Overall the light treatment helped, cured and reduced symptoms related to Parkinson's and since Parkinsons's is intimately related to lack of dopamine (as stated previously herein) it may be concluded that the applied light therapy had an effect on dopamine production in the brain. Thus, with an exemplary embodiment of the device according to the invention, light therapy was directed non-invasively at substantia nigra of a patient from an extra-cranial position, i.e. through the ear-canal, which resulted in altering of the production, release, re-uptake and/or metabolism of dopamine in substantia nigra of the user.

Example 4

A study was conducted where over a four week period with a daily 8-12 minute dose, 92% of the patients with SAD achieved full remission measured by the self-rated BDI-21, the most widely used questionnaire for rating depression. The daily time of usage was personalized at the study clinic.

Example 5

Trans-cranial light therapy was applied to three male patients, each patient approx. 40 years old.

The first patient was consuming alcohol in high amounts daily; this patient was possibly suffering from alcoholism. Light therapy was applied trans-cranially once per day (12 min daily dose) via the ear-canal using a device according to the invention. The applied light spectrum corresponds to the spectrum illustrated in FIG. 15C. After being treated with the light therapy he reported to have lost the desire to consume alcohol or alcoholic beverages. Even after the light therapy treatment stopped the alcoholic intake was drastically reduced compared to the initial abusive amounts.

The second patient, a highly trained generally healthy medical professional, performed a series of tests on himself: he consumed alcohol in small amounts (on the order of one standard drink) and rated the pleasure he felt before and after alcohol intake. This was on some days combined with a daily dose of light therapy via the ear canal using the light spectrum 15E1 as illustrated in FIG. 15E. He reported a significant decrease in subjectively felt pleasure of alcohol intake on days when light therapy was applied.

The third patient was generally in a healthy condition. He took several daily doses (1-3 daily doses, 12 minutes each) applying the light spectrum 15E1 as shown in FIG. 15E using a device according the invention. The patient experienced a total lack of desire to smoke. Furthermore, these high daily amounts of trans-cranially applied light caused a status, where the psychological reward mechanisms were reduced, such as enjoyment of working and sexual desire/libido. Reduced libido has also been experienced by other patients using several 12 min doses of light therapy daily.

Obsessive compulsive disorders (OCD), alcohol addiction and nicotine addiction are all related to the dopamine system. As trans-cranial applied light therapy provides significant effects on these disorders/addictions it can be concluded that the light therapy has an effect on the dopamine production.

Example 6

In order to study the impact of light therapy to the cognitive performance of humans a commonly used neuropsychological test called “trail-making test” was conducted with eleven test persons being subject to light therapy treatment.

A trail-making test is a neuropsychological test of visual attention and task switching. The task requires the test person to ‘connect-the-dots’ of a plurality (e.g. 25) consecutive targets on a sheet of paper or computer screen. Two versions are available: A, in which the targets are all numbers (1, 2, 3, etc.), and B, in which the subject alternates between numbers and letters (1, A, 2, B, etc.). The goal of the test person is to finish the test as quickly as possible, and the time taken to complete the test is used as the primary performance metric. The trail making test has become a common diagnostic tool in clinical settings.

In this example eleven test persons in normal healthy condition were subject to trans-cranial applied light therapy using a device according to the invention. The light spectrum shown in FIG. 15A was applied for a period of four weeks with a daily dose of 12 minutes for 5 days a week (not weekends). Trail-making tests of types A and B were conducted before and after four the week treatment period.

Results are illustrated in FIG. 16A. The eleven test persons along the vertical scale and with the measured progress for type A and type B trail making test. I.e. test person no. 11 performed approx. 16 and 17 percent better on the type B and type A trail making test, respectively, after the four weeks of light therapy, whereas test person no. improved his type A test with 35 percent but he conducted the type B test 20 percent slower after light therapy treatment. Overall 9 test persons out of 11 performed clearly better on type A test after the light therapy treatment. Two of the test persons showed lower performance on type A. 9 out of 11 performed clearly better on B type test after the treatment period. One performed worse than average. One did not show change in performance.

Dopamine is known to be related to the cognitive performance. Thus, since light therapy had a clear impact on cognitive performance of the healthy test persons it can be concluded that light therapy affects dopamine production in the brain.

Example 7

As a continuation of the previous example 5 a group of 90 generally healthy test persons were subject to trans-cranial applied light therapy using a device according to the invention. The light spectrum shown in FIG. 15D was applied for a period of four weeks with a daily dose of 12 minutes for 5 days a week (not weekends). Trail-making tests of types A and B were conducted before and after four the week treatment period. The test persons were divided into three groups with 30 persons each. A different light intensity of the light was applied to each group of test persons during the four weeks. Group 1: one lumen, group 2: four lumens and group 3: nine lumens of light. Results are illustrated in FIG. 16B. Overall the three groups performed 10-15 percent better in both tests compared to their performance before the light therapy. There are no significant differences between the groups, however with a small trend towards larger improvement with higher intensity of the light.

Dopamine is known to be related to the cognitive performance. Thus, since light therapy had a clear impact on cognitive performance of the healthy test persons it can be concluded that light therapy affects dopamine production in the brain.

Example 8

A double blind, placebo controlled, test for motoric reaction time was conducted with two groups of 11 persons (a total of 22). The test persons were male 18-32 years top athletes (national ice hockey league players). The test persons were subject to trans-cranial applied light therapy using a device according to the invention. The light spectrum in FIG. 15 e with the highest relative peak power was applied for a period of four weeks with a daily dose of 12 minutes for 7 days a week.

Generally ice hockey players are athletes with extremely low reaction times due to the nature of the sport. In spite of this the light therapy improved the reaction times of these very fast athletes. The results of the tests are illustrated in FIGS. 17 a-d with total reaction time to auditory stimulus in FIG. 17 a, motoric reaction time to auditory stimulus in FIG. 17 b, total reaction time to visual stimulus in FIG. 17 c and motoric reaction time to visual stimulus in FIG. 17 d. The mark “1” on the x-axis marks the average result of the test conducted prior to any light therapy whereas “2” marks the result of the test conducted after the period of light therapy. From the figures it can be seen that both the placebo group and the light therapy group show improvement in the measured reaction times. However, the improvement of the light therapy group is significantly better.

The improvement for motoric reaction time to visual stimulus is illustrates in FIG. 18 with the absolute improvement in ms (milliseconds) in FIG. 18 a and the relative improvement in FIG. 18 b. From FIG. 18 b it is seen that the placebo group showed a 10% improvement whereas the group the underwent trans-cranial light therapy showed an improvement of almost 25%. Thus a significant statistical improvement in the motoric reaction time with a difference between placebo and the light therapy group of p=0.023, when adjusted for age and p=0.044 without adjustment. The difference in enhanced reaction time was almost three fold.

Dopamine is known to be related to the motoric performance and reaction time. Thus, since light therapy had a clear impact on motoric performance and reaction time of the healthy test persons it can be concluded that light therapy affects dopamine production in the brain.

Example 9

A controlled dose-response study on the putative effect of extra visual bright light in the reduction of depressive symptoms in patients suffering from winter SAD was conducted. The bright light was administered trans-cranially via the ear canal daily during a four-week trial. Data was gathered during the darkest period of the year in northern Finland (latitude 64° 01′N) where the amount of daily light is very short.

The seasonal pattern of recurrent episodes of depression has become known as Seasonal Affective Disorder (SAD). The precise pathogenesis of SAD is still uncertain, despite several explanatory theories such as photoperiod and phase-shifted circadian rhythms, neurotransmitter functions, and genetic hypothesis. Given the fact that winter SAD is far more prevalent than summer SAD, the term SAD usually refers to winter SAD and is used accordingly hereafter. Episodes of SAD peak in winter and are characterized by typical and atypical depressive symptoms, i.e. lowered mood, energy loss, excessive sleep with difficulty waking, craving for carbohydrates, weight gain, irritability, social withdrawal, daytime fatigue, and loss of concentration.

The prevalence of SAD varies from 0 to approx. 10% in the general population. Climatological, social and cultural influences, genetic factors and geographical latitude have been reported to have an impact on the prevalence of SAD. SAD is more common among females and younger adults. SAD in females is usually characterized by minor depressive episodes, whereas males more commonly experience major depression.

Many controlled studies have found bright light therapy (BLT) effective in treating SAD. In a systematic review and meta-analysis, the effect size for the reduction of depressive symptoms by BLT in the treatment of SAD was 0.84. The antidepressant effect of bright light is potentiated by early morning administration in circadian time, about 2.5 hours after the sleep midpoint. According to the clinical guidelines, the recommend bright light exposure in treatment of SAD is 10,000 lux for 30 min per day. Although BLT is effective, about 70% of SAD patients complain that sitting in front of the bright light is uncomfortable, and almost one in five SAD patients stop BLT because of that.

The mechanism of action of BLT in the treatment of SAD is still under debate, and it is widely believed that the effect of light is mediated via the eye. However, there is evidence that in mammals significant amounts of light penetrate the skull bone and reach the brain.

Subjects and Methods

Adult persons suffering from seasonal depressive symptoms were recruited through advertisements in a local newspaper and were pre-screened for symptoms of SAD by a phone interview. The procedure of the study is presented in FIG. 12.

Structured diagnostic interviews were conducted at week 0 and 4 by two trained psychiatrists. Diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) for recurrent major depression (moderate or severe) was obtained using the Mini International Neuropsychiatric Interview (MINI). In addition, patients had to fulfil the diagnostic criteria for “seasonal pattern”.

The subjects included in the study had to score at least 20 points on the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder (SIGH-SAD, with a 21-item Hamilton Depression Rating Scale (HAMD-21) score of 10 or more and eight-item atypical symptom score of 5 or more. In this study, inclusion scores were analogous with the criteria used for evaluating the response to treatment in patients with SAD in earlier studies. Subjects with lifetime psychotic disorders, bipolar disorders, severe personality disorders, substance abuse or dependence, suicidal ideation during the past month, any psychotropic medications, and other bright-light therapy for the current SAD episode were excluded from this study. Pregnant females were also excluded. Written informed consent was obtained from the subjects after they had been given a full description of the study at the first visit during week 0. The research protocol was approved by the Ethics Committee of Oulu University Hospital, Finland.

The Light Therapy Device

The brain-targeted bright light treatment was given transcranially via ear canals by using the Valkee brain stimulation headset. This device was approved as a medical device in the European Union on 30 Mar. 2010, and since then it has been available for customers in Finland and other EU countries. The light was produced using light-emitting diodes (white LEDs), which were attached to earplugs. The bright light was transmitted to the ear canal by an optical guide. Daily BLT (bright light therapy) was taken during the forenoon at home, and each treatment session lasted 12 minutes.

Grouping of Subjects

The subjects involved in the study were randomly divided into three groups: low dose (group 1), intermediate dose (group 2) and high dose BLT (group 3). The randomization procedure followed a double-blind design. The amount of received light in the three groups was 1 lumen, 4 lumen and 9 lumen, respectively. Lumen is a measure of luminous flux, which is defined as the total amount of visible light emitted from a light source through a solid angle.

Measurement of SAD

The sum score of SIGH-SAD was used to evaluate the severity of SAD. The remission criterion was defined as score of 8 of 29-item SIGH-SAD score at week 4. For further analysis, SIGH-SAD, 14-item Structured Interview Guide for the Hamilton Anxiety Rating Scale (HAMA) and 21-item Becks Depression inventory, BDI were used to evaluate the response to treatment. The criterion for response was fulfilled when the patient had a decrease of 50% or more from the baseline scores in SIGH-SAD. HAMA and BDI. In addition to measuring safety and tolerability, information of bright light-related adverse events was gathered.

Statistical Analyses

All data are presented as percentages or as mean with 95% confidence intervals. Student t-test was used to compare baseline values between genders within light treatment groups. Categorical variables were compared by Chi-Square test or Fisher's Exact test when appropriate. The within-group and between group changes in variables during the study were analysed with repeated measures analysis of variance (ANOVA). Results with 2-sided p values <0.05 were considered statistically significant. Statistical analyses were performed using SAS version 9.2.

Results

Ninety patients with SAD, 68 of whom were females, participated in this study. Of these, one female patient dropped out due to a trip abroad. The mean age of participants was 43.0 years (SD 10.9, range: from 22 to 65 years). Table 1 shows the demographic and baseline variables of the treatment groups in both genders. The groups were similar in most respects, but differed in some variables. Statistically significant differences were found in age and BDI baseline sum score in treatment group 3 and in SIGH-SAD baseline sum score in treatment group 1 between females and males.

TABLE 1 Demographic and baseline variables for treatment groups Treatment Female (N) Male (N) Variables group Mean SD Mean SD p-value Age 1 42.0 (22) 10.6 43.3 (6) 10.8 0.7952 2 42.9 (25) 10.1 49.3 (6) 11.3 0.1795 3 38.4 (20) 10.2 51.0 (10) 11.3 0.0045 SIGH-SAD 1 37.8 5.5 32.0 7.2 0.0414 2 36.9 6.3 32.5 6.8 0.1407 3 36.3 6.1 34.4 8.8 0.4092 HAM-A 1 24.0 6.1 22.2 5.7 0.5034 2 23.0 6.5 21.0 7.7 0.5182 3 22.2 5.7 20.9 6.3 0.8619 BDI 1 20.5 8.3 17.5 8.0 0.2784 2 19.7 8.1 15.7 10.4 0.3057 3 22.2 8.7 13.7 8.7 0.0185

When compared to the baseline (week 0), statistically significant decreases were found in mean SIGH-SAD total scores after adjusting for age and gender in each treatment group (Table 2). The mean SIGH-SAD total scores decreased 17.6 points (47.4%, p<0.0001), 17.0 points (45.9%, p<0.0001) and 15.9 points (43.7%, p<0.0001) in the three treatment groups (1, 4, 9 lumen), respectively. The corresponding values for HAMA were 12.0 (49.9%, p<0.0137), 11.4 (49.5%, p<0.0056), 10.1 (46.5%, p<0.0001) and for BDI 13.7 (67.3%, p<0.0158), 13.4 (67.4%, p<0.1282), 11.9 (63.2%, p<0.0013). Although subjects in each group improved after exposure to bright light treatment, there were no statistical differences between these improvements.

TABLE 2 Depression and anxiety scale measures over four week study period Measure Group 1 (N = 28) Group 2 (N = 31) Group 3 (N = 30) Mean 95% CI Mean SD Mean SD Structured Interview Guide for the Hamilton Depression Rating Scale Seasonal Affective Disorder Version (SIGH-SAD) score Baseline 36.6 34.1-39.0 36.1 33.7-38.5 35.7 33.5-37.8 Endpoint 19.0 14.4-23.6 19.1 15.5-22.7 19.8 15.6-23.9 Hamilton Depression Rating Scale (HAMD) score Baseline 21.8 20.2-23.5 21.5 19.5-23.5 21.1 19.6-22.6 Endpoint 11.3  8.5-14.1 11.1  9.0-13.1 11.5  8.9-14.0 Atypical Symptom Scale score Baseline 14.8 13.1-16.4 14.5 13.2-15.9 14.6 13.2-16.0 Endpoint  7.7  5.3-10.1  8.0 6.2-9.9  8.3  6.3-10.3 Hamilton Anxiety Rating (HAMA) Scale Baseline 23.6 21.3-26.0 22.6 20.2-25.1 22.1 19.9-24.2 Endpoint 11.6  8.2-14.9 11.2  8.7-13.7 12.0  9.1-14.8 Beck's Depression Inventory Baseline 20.6 17.5-23.7 18.9 15.8-22.1 19.3 15.8-22.9 Endpoint  6.9  3.6-10.1  5.5 3.2-7.9  7.4  4.4-10.4 % 95% CI % 95% CI % 95% CI SIGH-SAD improvement 47.4 34.9-60.0 45.9 36.0-55.7 43.7 32.7-54.8 HAMA improvement 49.9 34.7-65.2 49.5 38.5-60.5 46.5 35.9-57.2 BDI improvement 67.3 53.0-81.6 67.4 55.5-79.4 63.2 49.9-76.6 Proportion 95% CI Proportion 95% CI Proportion 95% CI SIGH-SAD score ≦8 28.6 10.7-46.6 16.1  2.4-29.8 13.3  0.4-26.2

The proportions of the patients in each group achieving 50% or greater improvement in SAD symptoms are shown in FIG. 13. The response rate measured by SIGH-SAD varied from 35% to 45%. Corresponding variations for HAMA were 47-62% and for BDI 74-79%. Although the response rate was remarkable on each measurement, no statistically significant differences were found between treatment groups.

The self-rated BDI was assessed weekly in order to evaluate patients' depressive symptoms throughout the study (FIG. 14). A statistically significant decrease was found in each treatment group already at week 1 when compared to baseline, and the decrease continued throughout the study, although the decrease in depression scores did not differ between treatment groups.

The proportion of patients who reported potential bright light-related adverse events was 28.1% (n=25). There were no statistically significant differences in emergence of bright light-related adverse events between treatment groups. The most common adverse events were temporary headache, insomnia and nausea, which were reported by 10.1%, 5.6% and 3.4% of the patients, respectively. The other symptoms reported were dizziness, earache, abnormal sensation in the maxillary region, tinnitus, tiredness, irregular heartbeat and irritability.

Discussion

In this study it was found that both self-rated and psychiatrist-rated depressive and anxiety symptoms of SAD patients decreased significantly during the 4-week study period even after controlling for age and gender. However, there were no significant differences in improvement of anxiety or depressive symptoms between groups receiving different intensity of bright light via ear canals.

Bright light therapy has been reported to reduce depression symptoms as measured by the rating scales used in this study. The significant reduction in the symptoms of SAD in the present study parallels earlier two- to four-week studies with bright light therapy using traditional bright light devices. Comparing decreases of symptoms across studies is not optimal, but the comparison may be instructive. In the present study, when measured by SIGH-SAD-29, the decrease of raw scores varied between 15.9 and 17.6 points in three treatment groups, whereas in two earlier studies using same rating scale, the decrease was 10.4 points and 15.1 points. When comparing the percentage improvement, the percentage change in the present study, ranging between 44% and 47%, is in between the improvements seen in two earlier studies, i.e. 57% and over 30%. The SIGH-SAD response-rates observed in the present example are slightly lower than those seen in two earlier bright light studies using the same response criteria, i.e. 50% and 63%.

Researchers have found that bright light exposure also has anxiolytic effects among clinically anxious adults and patients suffering from winter depression. To the best of our knowledge, anxiety measurements have rarely been used in earlier bright light studies even though anxiety symptoms are quite common among patients suffering from depression. In the present study psychiatry-rated anxiety symptoms assessed by Hamilton anxiety scale (HAMA) decreased from moderate anxiety level to normal level during the four-week study period in each treatment group. The decrease in anxiety symptoms is comparable to the earlier pharmaceutical studies in the treatment of generalized anxiety disorder (GAD). The decrease in the mean HAMA score in the present study ranged from 10.1 to 12.0 points in three treatment groups, whereas in earlier pharmaceutical studies using pregabalin (600 mg/day) duloxetine (60-120 mg/day) and venlaflaxine (75-225 mg/day) the decrease of mean HAMA score was 11.6, 12.8 and 12.4 points, respectively. The response rates in the present study varied from 47% to 62%, while ranging from 39% to 59% in earlier GAD studies using pregabalin, from 40% to 65% with duloxetine, and from 54% to 61% with venlaflaxine. In future studies it would be beneficial to utilize valid anxiety measurements as well when evaluating the effects of bright light in SAD.

When self-reported BDI was used, our findings were in line with bright light groups in earlier studies, showing a decrease of raw scores from moderate depression level to level of minimal depression symptoms. The magnitude of the percentage improvement of depressive symptoms (from 63% to 68%) in the three treatment groups was comparable to the percent change in earlier bright light studies, i.e. 62% (BDI-25), 65% (BDI-21) and 69% (BDI-II). The BDI response rates in the present study are in between the response rates seen in earlier bright light studies, i.e. 58% and 82%.

The proportion of the subjects who met the criterion of remission in the present study varied from 13% to 29% in the three treatment groups, whereas in earlier studies using the same remission criteria, the proportions were 47%, 42% and 28%. On the other hand, it is known that bright light treatment is less sufficient for more severely ill patients and the severity of symptoms at baseline has effects on remission rates; SAD patients who experience more severe symptoms have lower remission rates. In addition, a low atypical balance score may also be a poor prognostic sign for response to bright light therapy. The SAD patients in the present study were more severely ill at baseline than reported in earlier studies. In the present study the baseline SIGH-SAD total scores varied from 35.7 to 36.5, whereas in three earlier SAD studies SIGH-SAD total scores ranged between 26.5 and 30.6 points. In addition, in the present study, the possibility of spontaneous remissions was diminished by excluding patients diagnosed with bipolar disorder not otherwise specified or bipolar II disorder.

The adverse effects of bright light are generally known to be mild and rarely lead to treatment discontinuation. However, 47% of SAD patients are refractory to light therapy, at least partly because of poor long-time compliance with light use. Traditional light therapy requires a considerable daily time commitment from the patient during the symptomatic months, but it has been observed that 58% of patients stopped the light treatment when using the light device become voluntary. In this study, transcranially administered BLT had an equal rate of potential adverse events (28%) when compared to earlier traditional BLT studies (25%). The most common side effects in this study were occasional headache, insomnia and nausea. In an earlier study using traditional BLT the emergence of headache was slightly lower, whereas insomnia and nausea were noted markedly more often. We think that this new bright light innovation might result in better compliance than traditional BLT, because it is convenient, allows moving during treatment, does not irritate the eyes, and the daily treatment times are relatively short.

A limitation of this study is that we did not have a control group. We agree with Meesters and associates that it is impossible to create real placebo condition for visible light. We are also aware of the fact that the bright light used in treatment of SAD is accompanied by a potentially large placebo response ranging from 21% to 41%. It is generally assumed that sham devices have higher response rates than placebo pills used in trials of treatment of depression. However. Brunoni and associates reported in their large review and meta-analysis that repetitive transcranial magnetic stimulation (rTMS) as a non-pharmacological treatment in major depression had a lower placebo response than pharmacological therapy. The placebo-response of the device used in this study has not been explored so far. Since treatment sessions in this study resemble the sessions of rTMS treatment, we believe that the improvement of depression and anxiety symptoms observed in our study are unlikely to be solely explained by the placebo effect. In future studies the size of the placebo response should be carefully scrutinized.

Some methodological limitations deserve discussion. There were older males than females and more severely ill females than males in one subgroup. In addition, the proportion of males (24.7%) was quite low. This may have biased our results, since it is known that the prevalence and severity of SAD may differ in different gender and age groups. Moreover, it is found that males seem to underreport SAD symptoms.

We are aware that the amount of daylight increases towards the spring. However, our study was conducted during the darkest season of the year. All patients lived in Northern Finland, which is located only about 170 km south of the Arctic Circle. In addition, the majority patients were indoor workers who hardly saw daylight during the study period, which is strength of our study.

In sum, this is the first randomized controlled clinical trial to show antidepressant and anxiolytic effect of transcranial bright light therapy on symptomatic SAD patients. We are thus not able to compare our results to earlier studies of transcranial light in the treatment of SAD. These results are however in line with the findings of earlier bright light studies using traditional bright light devices in the treatment of SAD and pharmaceutical studies in the treatment of GAD. In future, studies on neuroimaging, neurobiology and placebo-controlled trials are called for to further assess the efficacy and mechanism of action of transcranially delivered bright light.

The conclusions of this randomized controlled trial where 89 subjects suffering from severe seasonal affective disorder had a 12-min daily Valkee dose at home in three different randomly divided groups of one, four, and nine lumen, are that the response rates in the sub-groups were 74-79% for seasonal depression and 47-62% for anxiety symptoms, and included at least 50% reduction in BDI-21 and HAMA score at week four. The daily administration time was fixed to the morning, after waking up.

Example 10

In order to investigate a short term response of light stimulus of the human brain, functional connectivity changes of the brain were studied in the resting state with functional magnetic resonance imaging during bright light stimulus via the ear canal. The results from the full band resting state independent component analysis (ICA) dual regression analysis of normal healthy volunteers shows that brain tissue is inherently light-sensitive. Light stimulation to the brain seems to induce a gradual increase in functional connectivity of the lateral visual network during the course of the stimulus. The light group demonstrated a slowly increasing response whereas the corresponding time course of the sham controls did not exhibit such a clear increasing trend. Lateral visual and sensorimotor networks showed increased functional connectivity in the light stimulus group compared to sham controls. The lateral visual network demonstrated slowly increasing functional connectivity on average and the same temporal characteristic was shared by diverse cerebellar brain regions.

There seem to be a phototransduction mechanism that results in excitatory signaling and leads to signal cascade with broad effects via neurotransmitters like dopamine, serotonin or noradrenaline mediated by the substantia nigra, raphe nuclei or locus coeruleus.

The brain function can be examined for example using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Sources of BOLD contrast are blood flow, volume and oxygenation that arise from local increases in neuronal mass activity. BOLD signals between distant brain regions exhibit intrinsic functional connectivity that seems to serve both stable and dynamic purposes. Stable properties are related to functional integrity maintenance and dynamic properties are related to psychological phenotypes. We reasoned that resting state fMRI would be an adequate combination of spatial and temporal accuracy for examining constant light induced effects on functional connectivity. Often spontaneous function in fMRI is studied at frequencies above 0.01 Hz, however, importantly for the present study there are fMRI studies showing BOLD drifts below 0.01 Hz to be neuro-physiologically meaningful and that baseline drifts can be induced by the administration of various drugs. The method for functional connectivity analysis was chosen to be independent component analysis (ICA) combined with dual regression, which has been shown to be an appropriate method for exploratory analyses. ICA is used to decompose fMRI data into group-level components and following dual regression reveals the corresponding subject-level temporal and spatial manifestations.

Based on the theory and treatment of SAD patients with bright light via the ear canal, we hypothesized that non-visual bright light stimulation of the human brain via the ear-canal would alter brain activity within an fMRI scanning session. Our hypothesis was studied using resting-state BOLD fMRI without any assumptions of the spatial or temporal response patterns. Therefore, a data-driven functional connectivity analysis was performed on the full band data and on the whole brain. Additionally we tested whether an instant response to light stimulus would occur in a typical fMRI block paradigm measurement setting.

Normal healthy adult volunteers aged 29±6 years were told they will participate into a light stimulus study. The main study examining responses to constant light stimulus via the ear canal consisted of altogether 51 subjects who were scanned in three divisions. First, 10 subjects were scanned in December (after 4 pilot subjects), then 27 subjects in February and finally 14 subjects in May. All light stimulation imaging sessions took place in December and in February when it is remarkably dark in Oulu, Finland (65° northern latitude); sham control sessions were imaged during February and May. After exclusion of pilot data and one subject with failed light stimulation timing, 24 light stimulus and 26 sham controls were available for analysis. Additionally, 9 light stimulus subjects were scanned in March employing an fMRI block paradigm.

Bright light was exposed to the external ear canal with the aim to stimulate the brain tissue during BOLD fMRI scanning, while sight of the light stimulus was prevented (FIG. 20 a). FIG. 20 b depicts the brain regions situated close to the ear canal. Light was produced by two 3 W LEDs (main light spectrum peak at blue light 465 nm and a secondary peak at 550 nm) and delivered via 5 meters long polycarbonate colourless fiber optic light guides connected to ear-plugs in the subject's ears while inside the scanner. The produced output luminous flux (circa 7-8 lumens) in each ear canal was of an order of magnitude comparable with sunlight intensity in the ear canal under bright sunny day conditions when directed towards the sun, according to our measurements. A 12 V power supply placed outside the scanner room was connected via a wave tube to the LEDs that were installed on a printed circuit board and contained in aluminum packaging situated inside the scanner room just next to the wave tube on the wall of the control room.

Functional MRI Data Acquisition

There were two fMRI study setups, the primary setup consisting of constant light stimulus during the imaging session and the second was used to check whether a response can be detected with a basic fMRI on-off block-design paradigm. The first scan of every session was a T1-weighted anatomical 3D FSPGR scan of about 3 min (FOV 24 cm with 256*256 matrix, slice thickness 1 mm, TR 12.1 ms, TE 5.2 ms, and flip angle 20 degrees).

Scanning sessions with constant stimulus consisted of two consecutive resting-state scans with eyes properly covered (FIG. 20 a). In the beginning of each resting state scan the subject was instructed to stay still during the following scan. The first scan was always without light stimulus and it was used for achieving better scanner stability before the actual stimulus scan. During echo-planar imaging, the gradient coils warm up and cause marked signal drifts during the first five minutes of the scanning (data not shown). Thus, a valid comparison between the first and the second scan on the full frequency band was not possible. The first scan also worked as a control condition for transversal comparison between the groups. The second scan was light on for the light group and no light for controls. These consecutive BOLD fMRI scans (8 min 24 s each) without breaks were performed with the instruction for the subject to lay still. The scanner was GE 1.5T Signa HDx upgraded from a Signa LX system and equipped with an 8-channel head coil provided by the scanner manufacturer. The pulse sequence was GR-EPI, parallel imaging (image domain reconstruction) acceleration factor 2, 283 time-points (discarding the first three volumes). TR 1.8 s, TE 40 ms, flip angle 90 degrees, FOV 25.6 cm with 64*64 matrix giving 4 mm voxel in-plane, 4 mm thick slices with 0.4 mm inter-slice gap, 28 slices acquired in an interleaved manner. The scanning parameters of the block-design setup were otherwise similar but the duration was 15 minutes, TR 2 s and 31 slices without a gap. Resting-state data were collected while alternating light on and off every 30 seconds. Light switching was operated manually while checking the timing from the stopwatch.

Time-concatenation group ICA was performed in order to obtain the spatial a priori maps for the functional connectivity analysis. ICA was calculated using high-pass filtered data (cut-off period 150 s) since the aim was to investigate functional connectivity networks obtained from the typical resting state frequency band, free from scanner drifts. Dimensionality of ICA decomposition was set to 30 components that is in the range commonly applied in fMRI. Further functional connectivity analysis was carried out using ICA combined with dual regression (version 0.5b) technique that produces subject-specific spatial maps corresponding to each component from group ICA. This involves first using the obtained group ICA spatial maps in a linear model fit against the individual fMRI data sets (spatial regression) resulting in time-courses (TCs) specific for each independent component (IC) in each subject. Secondly, using these TCs, subject-specific spatial maps are calculated voxel-by-voxel (temporal regression). In both regressions, data and design are de-meaned, and before the 2nd regression the TCs are variance normalized.

Spatial Analysis

Significant differences were revealed from comparisons between the constant light stimulus group (N=23) and the sham control group (N=26) using ICA dual regression analysis on full band fMRI data. In particular, the lateral visual network IC (FIG. 21 a) that largely conforms to the combined ventral and dorsal visual stream was found to have greater functional connectivity in the light group. The significant difference of 192 voxels (5.2 cm³) was widespread across the extrastriate visual cortex. Also, the cerebellum (especially anteriorly) and a bilateral difference on the border of cerebellum and brainstem near the locus coeruleus (locus coeruleus is the main site for serotonin production) were shown in the results. The sensorimotor IC also showed greater functional connectivity (21 voxels, 0.57 cm³) in the light group than in controls, at the border of the superior parietal lobule and the postcentral gyrus (FIG. 22 a).

Temporal Analysis

Examination of the temporal characteristics of the lateral visual component (FIG. 21 b) showed a slow increase in the light group that is clearly more prominent than the corresponding control group curve, which also exhibited slightly increasing activity during the second resting state scan. The light group temporal behavior was not a linear trend but showed the steepest increase in functional connectivity after some minutes and reached a type of a plateau at around six minutes. Trend coefficients of the polynomial fits were greater in the light group although not significant; p-values were 0.12 for the first degree coefficient and 0.08 for the second. Frequency-wise, the light group mean spectrum was broadly elevated at frequencies below 0.035 Hz and most importantly at the lowest frequencies (FIG. 21 c). The sensorimotor IC (FIG. 22 a) did not show clear differences in the trend (FIG. 22 b), although the light group had a slightly greater first degree coefficient (p-value 0.38), while second degree coefficients were equal (p-value 0.96). Slightly elevated low-frequency power can be observed for sensorimotor IC (FIG. 22 c).

Comparison of Baseline Scans Between the Groups

The first resting scans were employed as a control condition for checking whether there are systematic differences between groups preceding the actual scan of interest. The lateral visual IC that showed marked differences in the second scans was not found to differ in the first scans and the group mean TCs were similar considering the trend (data not shown). There were no prominent differences between the groups in the first resting state scans; the control group exhibited greater connectivity of 0.6 cm³ in the default-mode network.

Discussion

Interpreting from the average brain (MNI 152) in standard space (FIG. 20 b), the regions encountering most of the light from the ear canal are the anterior cerebellum, inferior temporal lobe and pons in the brainstem. Also, the midbrain in the brainstem, posterior diencephalon and anterior occipital lobe can be within the range of light photons, especially at longer wavelengths.

Most of the detected differences from lateral visual IC are situated within that IC, but also other areas share the temporal characteristics of the lateral visual component. These include the cerebellum anteriorly and bilaterally, on the border between the cerebellum and the brainstem (FIG. 21 a). The latter difference lies close to the locus coeruleus, but detection of such a subtle structure is not feasible with present imaging resolution. The cerebellum is known to be involved in a vast range of tasks, in addition to motor functions, e.g. attention, executive control, language, visuo-spatial function and working memory. The loci of our cerebellar findings (FIG. 21 a) lie close to lobules with functional connections to the somatosensory cortex.

Example 11 Clinical Effect of Light Route and Dose

Different routes of light administration have been examined. Brain tissue of 10 subjects with SAD were illuminated via different delivery routes in a dark room and the eyes covered to avoid any ocular stimuli. Illumination was performed with highly targeted LEDs capable to administer bright light accurately (eye lid, ear, palate, temple) or an array of LEDs capable to administer bright light more broadly to the illuminated part of the head (palate, temple, back of the head). The response was measured with multiple physiological parameters such as EEG, heart rate, heart rate variation, body temperature and observable physiological changes. Subjects were also asked to evaluate their subjective response to treatment. The results are shown in Table 3.

TABLE 3 Route Result Eye lid No clinical efficacy comparable to ear route due to eye irritation. For clinical effect, intensity should exceed 3 lumens, which is already riskful for retina (2.7 lumen turned out to be threshold for pain). Palate No adverse events. Low observed clinical efficacy. Very inconvenient to use, and would cause lowered compliance to treatment. Ear High clinical efficacy. No adverse events. Easy to use. Auditory canal has the shortest distance to deep brain regions involved in most functions. Below skull edge, No clinical efficacy. at back of the head Temple No clear clinical efficacy; treatment focused onto frontal cortex and effects from midbrain, cerebellum, pons etc are not achieved. Non-optimal site to construct a device.

Light administration via both ear canals using a device as disclosed in WO 2008/029001 was chosen for further studies. The dosing study was done with 15 healthy volunteers and 5 SAD sufferers with a device capable of administering different time periods and intensities via the ear canal. Study subjects were lying awake in a silent and dark room with their eyes covered to block any external ocular or audio stimuli. The study was blinded for the subjects: They did not know if they were given bright light and with what parameters. Response to bright light after a daily treatment of maximum one week was assessed with structured interview and real-time monitoring of physiological stimuli such as heart rate, heart rate variation and EEG.

The results obtained with light intensities varying from 1 to 12 lumens, and duration of light exposure varying from 3 to >15 minutes are shown in Tables 4 and 5, respectively. The different light intensities were conducted for 6-12 minutes, and the different duration times were conducted with 3-9 lumens.

TABLE 4 Light intensity in ear canal Intensity in ear canal Result 1 lumen No or not measurable short-term clinical efficacy. 3 lumens No adverse events. Low observed clinical efficacy. Slight responses would need weeks use. 4-6 lumens High clinical efficacy. Immediate post-treatment subjective observations of psychotropic and cognitive responses. No adverse events. 6-9 lumens High clinical efficacy. Immediate post-treatment subjective observations of psychotropic and cognitive responses. Some subjects experience headache, dizziness, orthostatic hypotension or similar symptoms. 12 lumens Most subjects experience symptoms and feeling familiar with sunstroke, headache, dizziness or similar symptoms, orthostatic hypotension and even adverse effect on blood pressure, heat in the ear canal.

TABLE 5 Light duration in ear canal Duration Result 3 min No clinical efficacy 6 min No adverse events. First immediate experiences of alertness, “low dose” circadian entrainment and acute anxiolytic effect. Low observed clinical efficacy on severe mood disorders. 8 min High clinical efficacy. No adverse events. 12 min High clinical efficacy on severe mood disorders. Some patients experience headache and lightheadness. 12-15 min Many subjects experience symptoms and feeling familiar with sunstroke, headache, dizziness or similar symptoms, orthostatic hypotension, heat in the ear canal. >15 min Most subjects experience symptoms and feeling familiar with sunstroke, headache, dizziness or similar symptoms, orthostatic hypotension, heat in the ear canal, nausea and even vomiting.

The optimal light dose in the above experiments was 3-9 lumens for 6-12 minutes.

Dose response for SAD was further studied in a 3-arm dose response trial, where patients were divided into 0.7 lumen, 4 lumen and 9 lumen light intensity groups. Each group had 30 patients. Each patient was given a respective device to use once a day for 6-12 minutes for 4 weeks at home. The patients were evaluated by a qualified psychiatrist for their level of seasonal depression with Structural Interview Guide for the Hamilton Depression Rating Scale SIGH-SAD at the beginning and at the end of study, and they completed BDI21 self-rating scale weekly at home. The results indicated that up to approximately 80% had symptoms significantly decreasing in each study group. The patients in the 9 lumen and 4 lumen groups remitted significantly faster, typically in 1 to 3 weeks, compared to the 0.7 lumen group who remitted in 4 weeks.

Example 12 Clinical Trial with SAD Patients

The optimal dose was later selected into a clinical trial with 13 SAD patients. A pilot prospective study on the putative effect of intra-cranial bright light in the treatment of winter SAD was run.

The light was produced by using phosphor-based white led (465 nm blue light led basis) with a secondary light spectrum peak at 550 nm in a main unit by two 3 W power-LEDs, which is a medical device approved in the European Union. The amount of photic energy was 6.0-8.5 lumens in both ear canals, and the length of treatment was 8 to 12 minutes five times a week during a four-week study period. The patients did not receive any other treatments during the study period.

Subjects were recruited through advertisements in the city of Oulu, Finland (latitude 65° 01′N). The final patient series consisted of 13 (aged 37.1±7.2 years) physically healthy indoor workers suffering from major depressive disorder with seasonal pattern according to DSM-IV-TR criteria. Severity of depressive symptoms was assessed using the HAMD-17 and BDI-21. The ethical committee of Oulu University Hospital approved the study protocol.

The HAMD-17 mean sum score at screening was 23.1±1.6. Ten out of 13 SAD patients (76.9%) achieved full remission (i.e., HAMD-17 sum score ≦7), and 92.3% (12/13) at least 50% reduction in HAMD-17 sum scores at “Week 4”. By using a mixed regression model of repeated measures (AR-1) controlling for age, gender, HAMD-17 mean sum score at screening, significant differences were found comparing the HAMD-17 mean sum scores of “Week 0” with the corresponding scores at the “Week 3” (t=−2.05, p=0.045) and “Week 4” visits (t=−2.77, p=0.008) (FIG. 19). Correspondingly, significant differences were found comparing (age and gender controlled) the BDI-21 mean sum scores (15.2±6.7) of “Week 0” with the corresponding scores at the “Week 3” (t=−2.37, p=0.021) and “Week 4” visits (t=−3.65, p<0.001). The results are also shown in FIG. 19.

Example 13 fMRI Analysis of the Brain of SAD Patients During Light Therapy

fMRI research was conducted to show modulation of the human brain caused by light treatment with the selected, optimal light dose. For provision of reference information applicable in detection of SAD, fMRI was used to collect test data from 45 medication-free subjects with SAD, and 45 age-, gender- (39.78±10.64, 30 ♀, 15 ♂) and ethnicity-matched healthy control subjects (no concomitant medications) from the general population. The test groups were imaged with fMRI using the same test protocol during one winter-period. All subjects with SAD were scanned within one week after they were diagnosed.

During measurements, resting-state BOLD data were collected on a whole body fMRI system with an eight channel receive coil, using a defined sequence (EPI GRE sequence: TR 1800 ms, TE 40 ms, 280 time points, 28 oblique axial slices, slice thickness 4 mm, inter-slice space 0.4, whole brain coverage. FOV 25.6 cm×25.6 cm, with 64×64 matrix, parallel imaging factor 2, flip angle 90°). T1-weighted scans were imaged using 3D FSPGR BRAVO sequence (TR 12.1 ms, TE 5.2 ms, slice thickness 1.0 mm, FOV 24.0 cm, matrix 256×256, and flip angle 20°, and NEX 1) in order to obtain anatomical images for co-registration of the fMRI data to standard space coordinates. For resting state, the subjects were instructed to simply lay still inside the scanner with their eyes closed, think of nothing particular and not to fall asleep. Motion was minimized using soft pads.

ICA was used as a data-driven analysis tool for processing fMRI-generated voxel values. It was shown that by increasing the number of ICA estimated sources, one can probe the entire brain cortex with finely detailed sub-networks. ICA allows differentiating relevant functional brain signals from various sources of noise without a priori knowledge of the signal origin. It also separates noise sources from detected data and then provides spatial maps of functionally independent brain networks.

In the exemplary tests the results revealed that SAD patients compared to age-, gender- and ethnicity-matched healthy control subjects showed statistically significant increases in functional connectivity involving several RSNs. SAD-related increased functional connectivity was shown at two different functional levels while mainly focusing on the detailed RSNs level (70 ICs). Large-scale functional brain networks were localized using low model order ICA of 20 components. Significant increases in functional connectivity were detected in 4 out of 11 identified RSNs in patients with SAD. Segmentation of the brain functionality into detailed sub-networks using a high model order ICA of 70 components yielded 47 RSNs. Significant increases in functional connectivity were detected in 25 RSNs out of the 47 identified networks. Datasets of spatial maps on the detected RNSs and/or of the RNSs of altered functional connectivity are thus applicable as reference information related to a defined physiological disorder, in this example SAD.

Example 14 Light Therapy Effect on Migraine

The treatment modality tested was as follows for (a) preventive and (b) attack treatment:

(a) Preventive Treatment

-   -   One daily dose     -   6-12 minutes     -   3-10 lumens intra-cranial via non-ocular route via each ear         canal with a light source in each ear     -   Visible light spectrum imitating natural sunlight     -   Administered during the day at the time resulting into best         patient-evaluated treatment response

The most typical feedback was that a daily dose kept the attacks away completely. Examples of patient feedback for the above mentioned use is given below:

P1 started the light therapy in spring 2010, and almost completely got rid of her migraine attacks. After being without light therapy for a couple of months, the attacks returned. The light treatment functioned as a preventive medicine, but does not cure the attack. Regularly used it prevents the attacks or at least alleviates them.

P2 found that the light treatment kept the migraine attacks away. After no light therapy for five days, the attacks returned.

P3 who was suffering from repeated migraine attacks did not have any attack during the light treatment period.

(b) Migraine Attack in Progress-Treatment

-   -   One to three doses as described in the preventive treatment when         the migraine attack is arising or at its full, at intervals         depending on individual progression of the migraine attack.

The most typical feedback is that one to three doses when the attack is arousing or in progress aborts the attack or delays it. Examples of patient feedback for the above mentioned use is given below:

P4 found that he could postpone the migraine attack when he conducted the light therapy in the beginning of the attack.

P5 took medication during a migraine attack, and further conducted light therapy. She found that the light therapy improved the pain-relieving effect during the attack.

P6 found that the light therapy relieved an on-going attack.

Example 15 Light Treatment of Jet Lag

In jet lag, the body clock is out of synchronization as it experiences daylight and darkness contrary to the rhythms to which it has grown accustomed to. A number of volunteers tried the light-emitting ear plugs described in WO 2008/029001 with a light intensity of 3-9 lumens for 8-12 minutes at about the desired wake-up time at the destination. The feedback has been very positive. Here are two examples:

P7 conducted the light treatment for 8 minutes, 1.5 hours after the desired wake-up time for one week at a destination with 9 hours time difference from the departure. From the very first day onwards she fell no jetlag symptoms, that she usually has, especially the afternoon-dizziness was missing. She continued with the light treatment when back home, and the results were as good. There were no problems this time to get back to the rhythm.

P8 used the same light treatment when travelling from Europe to the American west coast. He did not experience jetlag, and his colleagues were wondering why he was not feeling tired during afternoon meetings.

Example 16 Treatment Modalities

The following treatment modalities using intra-cranial administration of bright light via the ear canals with two led lights into two ears with 3-9 lumens (Im) intensity for 6-12 minutes were found effective:

-   -   1. once a day for SAD during the season or episode when the         disorder is symptomatic;     -   2. once a day for PMS during the menstrual cycle, or up to five         days prior to menstruation, or when individual symptoms start to         occur;     -   3. once a day for migraine as preventive treatment;     -   4. one to several doses daily when treating migraine         seizure/attack;     -   5. once a day at the desired wake-up time at destination for jet         lag or desired alertness time shift work;     -   6. once a day for post-traumatic stress disorder;     -   7. once a day for MDD;     -   8. one to three times a day for OCD;     -   9. One dose (might be repeated when necessary) for acute         treatment in anxiety or anxiety disorder (AD);     -   10. Once or more times a day to treat acute or chronic         inflammation;     -   11. +1-(−2) h from desired wakeup-time for shift work sleep         disorder. If entrainment this way causes too early wakeup, then         on the “desired noon”. All wavelength with blue spectra and         short wavelengths emphasized.

Even lower light intensities may be used for the following indications:

TABLE 6 Light Indication Intensity Timing Properties Fertility 1-9 lm 1-3 times daily at daytime All wave-lengths, Light/Dark-ratio enhancement blue spectra allows enabled with 2 or more smaller intensity in sessions. the evening. Autoimmune: 1-9 lm 1-3 times daily at daytime All wave-lengths psoriasis, with green spectra atopic skin, skin emphasized. disorders Alzheimer 1-9 lm 1 or more times daily, treatment All wave-lengths total energy according to with green and disease severeness. infrared empha- sized. Bipolar affective 1-9 lm 1-3 times daily. Morning dose All wave-lengths disease carefully timed according to mood response. Postpartum 1-9 lm 1-3 times daily at daytime All wave-lengths depression Anxiety 1-9 lm High intensity (4-9 lm) on acute All wave-lengths symptoms, lower (1-6 lm) for maintenance. Optimizing/ 1-12 lm  From 1 (with large intensities) to All wave-lengths increasing dopamine several (with smaller intensities) levels in OCD and times daily. 2 doses (morning + Parkinson's evening) with 3-6 lm threshold to markedly activate substantia nigra and enhance dopamine action in brain. Optimizing/increasing 1-12 lm  1-3 times daily. Increased raphe All wave-lengths 5-HT (serotonin) nuclei activity and enhanced levels in monoamine metabolism causing mood disorders, increased 5-HT level also chronic pain, migraine elsewhere in brain. and other diseases Optimizing/ 1-9 lm 1-3 times daily. Increased locus All wave-lengths increasing coeruleus activity. noradrenaline/ norepinephrine levels in mood and neurological disorders Insomnia, difficulty in 1-4 lm Shorter treatment periods with All wave-lengths, falling asleep or 5-9 5-9 lm (1-4 lm/4-12 min, 5-9 blue spectra should lm lm/1-4 min). 3-0 hrs before be diluted on higher bedtime, alternatively morning/ intensities to avoid daytime use with high doses. entrainment if evening dose used.

FURTHER DETAILS OF THE INVENTION

The invention will now be described in further detail with reference to the following items:

-   1. A device for non-invasive/trans-cranial light therapy comprising     one or more radiation units adapted to direct optical radiation at     one or more neuroanatomical brain structures of a user from at least     one extra-cranial position of the user, said device applied for use     in altering and/or controlling the (natural) production, release,     re-uptake and/or metabolism of dopamine, serotonin or noradrenaline     in at least one of said one or more neuroanatomical brain structures     and/or in the body of the user. -   2. The device according to item 1, wherein said at least one     extra-cranial position is below the cerebrum of the user. -   3. The device according to any of the preceding items, wherein said     at least one extra-cranial position is non-ocular. -   4. The device according to any of the preceding items, further     comprising a housing in optical and/or electrical connection with     said one or more radiation units. -   5. The device according to any of the preceding items, further     comprising one or more light sources for generating the optical     radiation. -   6. The device according to any of the preceding items, further     comprising means for adapting the intensity of the optical     radiation. -   7. The device according to any of the preceding items, further     comprising means for adapting the spectral composition of the     optical radiation. -   8. The device according to any of the preceding items, wherein the     optical radiation emitted from a radiation unit is applied with a     predefined setting. -   9. The device according to any of the preceding items, wherein the     optical radiation emitted from a radiation unit is applied with one     or more of the following parameters being predefined: duration,     intensity, total power and spectral composition. -   10. The device according to any of the preceding items, wherein the     optical radiation emitted from a radiation unit is applied with one     or more of the following parameters being predefined for a plurality     of predefined wavelength intervals: duration, intensity, total     power, spectral output and spectral composition. -   11. The device according to any of the preceding items, wherein the     optical radiation emitted from a radiation unit is applied with a     predefined ratio of:     -   a first spectral output integrated over a first wavelength         interval, and     -   a second spectral output integrated over a second wavelength         interval. -   12. The device according to any of the preceding items, wherein the     optical radiation emitted from a radiation unit is applied with a     predefined ratio of:     -   a first spectral output integrated over a first wavelength         interval,     -   a second spectral output integrated over a second wavelength         interval, and     -   a third spectral output integrated over a third wavelength         interval. -   13. The device according to any of the preceding items, wherein the     optical radiation is bright light applied at each extra-cranial     position with a luminous flux of between 0.1 and 12 lumens, or     between 0.1 and 1 lumens, or between 1 and 2 lumens, or between 2     and 3 lumens, or between 3 and 4 lumens, or between 4 and 5 lumens,     or between 5 and 6 lumens, or between 6 and 7 lumens, or between 7     and 8 lumens, or between 8 and 9 lumens, or between 9 and 10 lumens,     or between 10 and 11 lumens, or between 11 and 12 lumens. -   14. The device according to any of the preceding items, wherein the     optical radiation is bright light applied at each extra-cranial     position with a luminous flux of at least 3 lumens, or at least 4     lumens, or at least 5 lumens, or at least 6 lumens, or at least 7     lumens, or at least 8 lumens, or at least 9 lumens, or at least 10     lumens, or at least 11 lumens, or at least 12 lumens. -   15. The device according to any of the preceding items, wherein the     optical radiation is applied with a duration of between 1 and 15     minutes, or between 1 and 2 minutes, or between 2 and 3 minutes, or     between 3 and 4 minutes, or between 4 and 5 minutes, or between 5     and 6 minutes, or between 6 and 7 minutes, or between 7 and 8     minutes, or between 8 and 9 minutes, or between 9 and 10 minutes, or     between 10 and 11 minutes, or between 11 and 12 minutes, or between     12 and 13 minutes, or between 13 and 14 minutes, or between 14 and     15 minutes. -   16. The device according to any of the preceding items, wherein the     spectral composition of the optical radiation is adapted to the     absorption spectrum of one or more light sensitive opsins. -   17. The device according to item 16, wherein at least one of said     opsins is present in at least one of said neuro-anatomical     structures. -   18. The device according to any of the preceding items, wherein the     optical radiation comprises light from a plurality of wavelength     intervals. -   19. The device according to item 18, further comprising means for     adapting the intensity, timing, total power and/or total energy of     optical radiation provided in each wavelength interval. -   20. The device according to any of items 18 to 19, further     comprising means for adapting the ratio of the intensity, timing,     total power and/or total energy of optical radiation provided in the     wavelength intervals. -   21. The device according to any of the preceding items, wherein the     optical radiation comprises light in a first wavelength with a start     point of between 380 nm and 440 nm, such as 385 nm, 390 nm, 395 nm,     400 nm, 405 nm, 410 nm, 415 nm, 420 nm, 425 nm, 430 nm or 435 nm,     and an endpoint of between 445 nm and 530 nm, such as 450 nm, 455     nm, 460 nm, 465 nm, 470 nm, 475 nm, 480 nm, 485 nm, 495 nm, 500 nm,     505 nm, 510 nm, 515 nm, 520 nm or 520 nm. -   22. The device according to any of the preceding items, wherein the     optical radiation comprises light in a second wavelength interval     with a start point of between 460 nm and 520 nm, such as 465 nm, 470     nm, 475 nm, 480 nm, 485 nm, 490 nm, 500 nm, 505 nm, 510 nm, or 515     nm, and an endpoint of between 590 nm and 800 nm, such as 600 nm,     610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690     nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm,     780 nm or 790 nm. -   23. The device according to any of the preceding items, wherein the     optical radiation comprises light with a predefined ratio of a first     spectral output in a first wavelength interval and a second spectral     output in a second wavelength interval. -   24. The device according to any of the preceding items, wherein said     predefined ratio is between 0.1 and 1, such as between 0.1 and 0.15,     such as between 0.15 and 0.2, such as between 0.2 and 0.25, such as     between 0.25 and 0.3, such as between 0.3 and 0.35, such as between     0.35 and 0.4, such as between 0.4 and 0.45, such as between 0.45 and     0.5, such as between 0.5 and 0.35, such as between 0.55 and 0.6,     such as between 0.6 and 0.65, such as between 0.65 and 0.7, such as     between 0.7 and 0.75, such as between 0.75 and 0.8, such as between     0.8 and 0.85, such as between 0.85 and 0.9, such as between 0.9 and     0.95, such as between 0.95 and 1. -   25. The device according to any of the preceding items, wherein the     optical radiation comprises light in a third wavelength interval. -   26. The device according to any of the preceding items, wherein the     optical radiation comprises light in a fourth wavelength interval. -   27. The device according to any of the preceding items, wherein the     optical radiation is generated by a plurality of different light     sources. -   28. The device according to any of the preceding items, wherein the     optical radiation is generated by a plurality of light sources with     different spectral characteristics. -   29. The device according to any of items 27 to 28, wherein the     spectral composition of the optical radiation emitted from the     radiation unit(s) is adapted by controlling the light sources     independently. -   30. The device according to any of the preceding items, wherein said     one or more light sources is accommodated in the housing. -   31. The device according to any of the preceding items, wherein one     or more light sources is accommodated in each radiation unit. -   32. The device according to any of the preceding items, wherein each     radiation unit comprises a single light source. -   33. The device according to any of the preceding items, wherein at     least one radiation unit comprises a light guide for guiding at     least a part of said optical radiation. -   34. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be attached to the skin of     the user at said extra-cranial position. -   35. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be arranged at an external     ear of the user. -   36. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be arranged on an earlope of     the user. -   37. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be arranged at least partly     inside an external auditory canal of the user. -   38. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be arranged such that at     least part of said optical radiation is guided into an external     auditory canal of the user. -   39. The device according to any of the preceding items, wherein at     least one radiation unit is adapted to be arranged such that at     least part of said optical radiation is guided trans-cranially     through the at least one of the followings cranial bones: the     temporal bone, squama temporalis of the temporal bone, mastoid     portion of the temporal bone, petrous portion of the temporal bone,     tympanic part of the temporal bone, the zygomatic bone, the sphenoid     bone, the frontal bone, the parietal bone. -   40. The device according to any of the preceding items, further     comprising a headband structure accommodating the radiation unit(s). -   41. The device according to any of the preceding items, wherein said     extra-cranial position is selected from the group of: the external     auditory canal, behind the pinna, behind the earlobe, at Reid's base     line, the temporal bone, squama temporalis of the temporal bone,     mastoid portion of the temporal bone, petrous portion of the     temporal bone, tympanic part of the temporal bone, the zygomatic     bone, the sphenoid bone, the frontal bone. -   42. The device according to any of the preceding items, wherein said     one or more neuroanatomical brain structures are selected from the     group of: the brain stem, medulla oblongata, pons, midbrain,     substantia nigra, raphe nuclei, nucleus raphe obscurus, raphe     magnus, raphe pontis, raphe pallidus, nucleus centralis superior,     nucleus raphe dorsalis, nuclei linearis intermedius and linearis     rostralis. -   43. The device according to any of preceding items for use in     treatment of anxiety, depression, delirium, Alzheimer's disease,     ADHD, infertility, migraine, seasonal affective disorder (SAD),     cancer, obesity, circadian rhythm sleep disorders, jet lag, shift     work disorder, Parkinson's disease, burning mouth syndrome,     fibromyalgia, restless legs syndrome, social anxiety, hypertension     (HTN), cognitive impairment, migraine, headache, social phobia,     Generalized anxiety disorder (GAD), chronic pain and/or decreased     cognitive performance. -   44. A method for treatment of a disorder comprising applying a     physical stimulus to a neuro-anatomical brain structure, wherein the     physical stimulus is sufficient for inducing a change in the level,     such as an increase or decrease in the level, and/or controlling the     (natural) production, release, re-uptake and/or metabolism of     dopamine, serotonin or noradrenaline in said neuro-anatomical brain     structure. -   45. The method according to item 44, wherein the physical stimulus     is applied non-invasively. -   46. The method according to any of items 44 to 45, wherein the     physical stimulus is applied from an extra-cranial position. -   47. The method according to any of items 44 to 46, wherein the     physical stimulus is applied from an extra-cranial position below     the cerebrum. -   48. The method according to any of items 44 to 47, wherein the     physical stimulus is applied with a predefined setting. -   49. The method according to any of items 44 to 48, wherein the     physical stimulus is optical radiation, such as visible light, UV     light or infrared light. -   50. The method according to any of items 44 to 49, wherein the     spectral composition of the physical stimulus is adapted to the     absorption spectrum of one or more light sensitive opsins. -   51. The method according to any of items 44 to 50, wherein the     physical stimulus is optical radiation with one or more of the     following parameters being predefined: duration, intensity, total     power and spectral composition. -   52. The method according to any of items 44 to 51, wherein the     physical stimulus is optical radiation with one or more of the     following parameters being predefined for a plurality of predefined     wavelength intervals: duration, intensity, total power, spectral     output and spectral composition. -   53. The method according to any of items 44 to 52, wherein the     physical stimulus is optical radiation wherein the ratio of:     -   a first spectral output integrated over a first wavelength         interval, and     -   a second spectral output integrated over a second wavelength         interval, is predefined. -   54. The method according to any of items 44 to 53, wherein the     physical stimulus is optical radiation wherein the ratios of:     -   a first spectral output integrated over a first wavelength         interval,     -   a second spectral output integrated over a second wavelength         interval, and     -   a third spectral output integrated over a third wavelength         interval, are predefined. -   55. The method according to any of items 44 to 54, wherein the     optical radiation comprises light in a first wavelength with a start     point of between 380 nm and 440 nm, such as 385 nm, 390 nm, 395 nm,     400 nm, 405 nm, 410 nm, 415 nm, 420 nm, 425 nm, 430 nm or 435 nm,     and an endpoint of between 445 nm and 530 nm, such as 450 nm, 455     nm, 460 nm, 465 nm, 470 nm, 475 nm, 480 nm, 485 nm, 495 nm, 500 nm,     505 nm, 510 nm, 515 nm, 520 nm or 520 nm. -   56. The method according to any of items 44 to 55, wherein the     optical radiation comprises light in a second wavelength interval     with a start point of between 460 nm and 520 nm, such as 465 nm, 470     nm, 475 nm, 480 nm, 485 nm, 490 nm, 500 nm, 505 nm, 510 nm, or 515     nm, and an endpoint of between 590 nm and 800 nm, such as 600 nm,     610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690     nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm,     780 nm or 790 nm. -   57. The method according to any of items 44 to 56, wherein the     optical radiation comprises light with a predefined ratio of a first     spectral output in a first wavelength interval and a second spectral     output in a second wavelength interval. -   58. The method according to any of items 44 to 57, wherein said     predefined ratio is between 0.1 and 1, such as between 0.1 and 0.15,     such as between 0.15 and 0.2, such as between 0.2 and 0.25, such as     between 0.25 and 0.3, such as between 0.3 and 0.35, such as between     0.35 and 0.4, such as between 0.4 and 0.45, such as between 0.45 and     0.5, such as between 0.5 and 0.35, such as between 0.55 and 0.6,     such as between 0.6 and 0.65, such as between 0.65 and 0.7, such as     between 0.7 and 0.75, such as between 0.75 and 0.8, such as between     0.8 and 0.85, such as between 0.85 and 0.9, such as between 0.9 and     0.95, such as between 0.95 and 1. -   59. The method according to any of items 46 to 58, wherein said     extra-cranial position is selected from the group of: the external     auditory canal, behind the pinna, behind the earlobe, at Reid's base     line, the temporal bone, squama temporalis of the temporal bone,     mastoid portion of the temporal bone, petrous portion of the     temporal bone, tympanic part of the temporal bone, the zygomatic     bone, the sphenoid bone, the frontal bone. -   60. The method according to any of items 44 to 59, wherein said     neuro-anatomical brain structure is selected from the group of: the     brain stem, medulla oblongata, pons, midbrain, substantia nigra,     raphe nuclei, nucleus raphe obscurus, raphe magnus, raphe pontis,     raphe pallidus, nucleus centralis superior, nucleus raphe dorsalis,     nuclei linearis intermedius and linearis rostralis. -   61. The method according to any of items 44 to 60, wherein the     chemical compound is selected from the group of endogenous     chemicals, hormones, adrenalin, neurotransmitters, monoamines,     norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline),     histamine. -   62. The method according to any of items 44 to 61, wherein the     disorder is selected from the group of anxiety, depression,     delirium, Alzheimer's disease, ADHD, infertility, migraine, seasonal     affective disorder (SAD), cancer, obesity, circadian rhythm sleep     disorders, jet lag, shift work disorder, Parkinson's disease,     burning mouth syndrome, fibromyalgia, restless legs syndrome, social     anxiety, hypertension (HTN), cognitive impairment, migraine,     headache, social phobia, Generalized anxiety disorder (GAD), chronic     pain and/or decreased cognitive performance. -   63. The method according to any of items 44 to 62, wherein the     physical stimulus is applied by means of the device according to any     of items 1 to 41. -   64. A device comprising radiation means for directing light via the     ear canal of a subject for use in light therapy comprising     non-invasive intra-cranial administration of bright light using a     light intensity of 0.7-12 lumens for 1-15 minutes. -   65. The device of item 64, for use in light therapy comprising     directing light having an intensity of 3-9 lumens for a treatment     time of 6-12 minutes. -   66. The device of any of items 64 to 65, for use in light therapy     comprising directing light having an intensity of 4-9 lumens for a     treatment time of 8-12 minutes. -   67. The device of any of the preceding items, for use in treating a     central nervous system (CNS) condition, a mood disorder, a circadian     rhythm sleep disorder, or an inflammatory disease. -   68. The device of any of the preceding items, for use in treating a     subject suffering from seasonal affective disorder (SAD). -   69. The device of any of the preceding items, for use in treating a     subject suffering from SAD with light having an intensity of 3-9     lumens for a treatment time of 6-12 minutes at least once a day for     at least five days a week during the season when SAD is symptomatic. -   70. The device of any of the preceding items, for use in treating a     subject suffering from migraine. -   71. The device of any of the preceding items, for use in light     therapy comprising directing light having an intensity of 3-9 lumens     for a treatment time of 6-12 minutes once a day to prevent migraine,     or 1-3 times daily to relief a migraine attack. -   72. The device of any of the preceding items, for use in treating a     subject suffering from jetlag. -   73. The device of item 72, for use in light therapy comprising     directing light having an intensity of 3-9 lumens for a treatment     time of 6-12 minutes at the desired wakeup time. -   74. The device of any of items 64 to 73, for use in treating a     condition selected from seasonal affective disorder (SAD), major     depressive disorder (MDD), bipolar affective disorder, obsession     compulsive disorder (OCD), migraine, post-traumatic stress,     postpartum depression, Alzheimer's disease, Parkinson's disease,     anxiety, jetlag, shift work sleep disorder, insomnia, autoimmune     diseases, psoriasis, atopic skin, skin disorders, premenstrual     syndrome (PMS), and fertility disorders. -   75. A method of treating a subject in need of light therapy, said     method comprising providing a medical device comprising radiation     means for directing light via the ear canal of the subject, applying     the device to the subject, and directing non-invasively,     intra-cranially via the subject's ear canal bright light having an     intensity of 0.7-12 lumens for a treatment time of 1-15 minutes. -   76. The method of item 75, comprising directing light having an     intensity of 3-9 lumens for a treatment time of 6-12 minutes. -   77. The method of item 75, comprising directing light having an     intensity of 4-9 lumens for a treatment time of 8-12 minutes. -   78. The method of any of items 75 to 77, comprising treating a     central nervous sys-tem (CNS) condition, a mood disorder, a     circadian rhythm sleep disorder, or an inflammatory disease. -   79. The method of any of items 75 to 78, comprising treating a     subject suffering from seasonal affective disorder (SAD). -   80. The method of item 79, comprising treating a subject suffering     from SAD with light having an intensity of 3-9 lumens for a     treatment time of 6-12 minutes at least once a day for at least five     days a week during the sea-son when SAD is symptomatic. -   81. The method of any of items 75 to 80, comprising treating a     subject suffering from migraine. -   82. The method of item 81, comprising directing light having an     intensity of 3-9 lumens for a treatment time of 6-12 minutes once a     day to prevent migraine, or 1-3 times daily to relief a migraine     attack. -   83. The method of any of items 75 to 82, comprising treating a     subject suffering from jetlag. -   84. The method of item 83, comprising directing light having an     in-tensity of 3-9 lumens for a treatment time of 6-12 minutes at the     desired wakeup time. -   85. The method of any of items 75 to 84, comprising treating a     condition selected from seasonal affective disorder (SAD), major     depressive disorder (MDD), bio-polar affective disorder, obsession     compulsive disorder (OCD), migraine, post-traumatic stress,     postpartum depression. Alzheimer's disease, Parkinson's disease,     anxiety, jetlag, shift work sleep disorder, insomnia, autoimmune     dis-eases, psoriasis, atopic skin, skin disorders, premenstrual     syndrome (PMS), and fertility disorders. 

1. A device for non-invasive/trans-cranial light therapy comprising at least one radiation unit adapted to direct optical radiation toward at least one neuroanatomical brain structure of a user from at least one extra-cranial position below the cerebrum of the user, said device applied for use in at least one of altering and controlling at least one of the production, release, re-uptake, and metabolism of serotonin in at least one of said at least one neuroanatomical brain structure and in the body of the user.
 2. The device according to claim 1, wherein said at least one extra-cranial position is non-ocular.
 3. The device according to claim 2, wherein said at least one extra-cranial position is the auditory canal.
 4. The device according to claim 1, further comprising a housing in at least one of optical and electrical connection with said at least one radiation unit and with at least one light source, such as an LED, for generating the optical radiation.
 5. The device according to claim 1, further comprising means for adapting at least one of the intensity, the radiant flux, the luminous flux, and the spectral power of the optical radiation emitted from said at least one radiation unit.
 6. The device according to claim 1, further comprising means for adapting the spectral composition of the optical radiation emitted from said at least one radiation unit.
 7. The device according to claim 1, wherein the optical radiation emitted from a radiation unit is applied with a predefined spectral composition.
 8. The device according to claim 1, wherein the optical radiation emitted from a radiation unit is applied with at least one of duration, intensity, total power, radiant flux, luminous flux, spectral power output, and spectral composition being predefined for a plurality of predefined wavelength intervals.
 9. The device according to claim 1, wherein the optical radiation emitted from a radiation unit is applied with a predefined ratio of: a first spectral output integrated over a first wavelength interval, and a second spectral output integrated over a second wavelength interval.
 10. The device according to claim 1, wherein the optical radiation emitted from a radiation unit is applied with a predefined ratio of: a first spectral output integrated over a first wavelength interval, a second spectral output integrated over a second wavelength interval, and a third spectral output integrated over a third wavelength interval.
 11. The device according to claim 1, wherein the optical radiation is generated by a plurality of light sources with different spectral characteristics.
 12. The device according to claim 1, wherein the spectral composition of the optical radiation is adapted to the absorption spectrum of one or more light sensitive opsins present in at least one of said neuro-anatomical structures.
 13. The device according to claim 1, wherein the optical radiation comprises light with a predefined ratio of: a first spectral output in a first wavelength interval, and a second spectral output in a second wavelength interval.
 14. The device according to claim 13, wherein said predefined ratio is between 0.1 and 1, such as between 0.1 and 0.15, such as between 0.15 and 0.2, such as between 0.2 and 0.25, such as between 0.25 and 0.3, such as between 0.3 and 0.35, such as between 0.35 and 0.4, such as between 0.4 and 0.45, such as between 0.45 and 0.5, such as between 0.5 and 0.35, such as between 0.55 and 0.6, such as between 0.6 and 0.65, such as between 0.65 and 0.7, such as between 0.7 and 0.75, such as between 0.75 and 0.8, such as between 0.8 and 0.85, such as between 0.85 and 0.9, such as between 0.9 and 0.95, such as between 0.95 and
 1. 15. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of at least 5 lumens.
 16. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of at least one of: between 0.1 and 12 lumens, between 0.1 and 1 lumens, between 1 and 2 lumens, between 2 and 3 lumens, between 3 and 4 lumens, between 4 and 5 lumens, between 5 and 6 lumens, between 6 and 7 lumens, between 7 and 8 lumens, between 8 and 9 lumens, between 9 and 10 lumens, between 10 and 11 lumens, and between 11 and 12 lumens.
 17. The device according to claim 1, wherein the optical radiation is applied with a duration of between 6 and 13 minutes.
 18. The device according to claim 1, wherein the optical radiation is applied with a duration of at least one of: between 1 and 15 minutes, between 1 and 2 minutes, between 2 and 3 minutes, between 3 and 4 minutes, between 4 and 5 minutes, between 5 and 6 minutes, between 6 and 7 minutes, between 7 and 8 minutes, between 8 and 9 minutes, between 9 and 10 minutes, between 10 and 11 minutes, between 11 and 12 minutes, between 12 and 13 minutes, between 13 and 14 minutes, and between 14 and 15 minutes.
 19. The device according to claim 1, wherein at least one radiation unit is adapted to be arranged such that at least part of said optical radiation is guided trans-cranially through at least one cranial bone including at least one of a temporal bone, a squama temporalis of the temporal bone, a mastoid portion of the temporal bone, a petrous portion of the temporal bone, a tympanic part of the temporal bone, a zygomatic bone, a sphenoid bone, a frontal bone, and a parietal bone.
 20. The device according to claim 1, wherein said at least one neuro-anatomical brain structures is selected from the group consisting of substantia nigra, locus coeruleus, globus pallidus, and striatum.
 21. The device according to claim 1, is for use in treatment of at least one of anxiety, depression, delirium, Alzheimer's disease, ADHD, infertility, migraine, seasonal affective disorder (SAD), cancer, obesity, circadian rhythm sleep disorders, jet lag, shift work disorder, Parkinson's disease, burning mouth syndrome, fibromyalgia, restless legs syndrome, social anxiety, hypertension (HTN), cognitive impairment, migraine, headache, social phobia, Generalized anxiety disorder (GAD), chronic pain, and decreased cognitive performance.
 22. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of between 3 and 9 lumens.
 23. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of between 0 and 3.5 lumens.
 24. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of between 3 and 6 lumens.
 25. The device according to claim 1, wherein the optical radiation is bright light applied at each extra-cranial position with a luminous flux of between 4 and 6 lumens for between 8 and 12 minutes.
 26. The device according to claim 1, wherein the optical radiation is bright light with a luminous flux of between 3 and 6 lumens applied by insertion of at least one radiation means directly into an auditory canal.
 27. A method of non-invasive/trans-cranial light therapy comprising the steps of: providing at least one radiation unit; producing optical radiation with the at least one radiation unit; directing the optical radiation toward at least one neuroanatomical brain structure of a user from at least one extra-cranial position below the cerebrum of the user; and with the radiation unit, at least one of altering and controlling at least one of the production, release, re-uptake, and metabolism of serotonin in at least one of said at least one neuroanatomical brain structure and in the body of the user.
 28. The method of claim 27, wherein the step of directing the optical radiation toward at least one neuroanatomical brain structure of a user includes the step of placing at least a portion of the radiation unit directly into an auditory canal of the user.
 29. The method of claim 27, wherein the step of directing the optical radiation toward at least one neuroanatomical brain structure of a user includes the step of adapting the spectral composition of the optical radiation to the absorption spectrum of one or more light sensitive opsins present in at least one of said neuro-anatomical structures.
 30. The method of claim 27, wherein the step of directing the optical radiation toward at least one neuroanatomical brain structure of a user includes the step of directing bright light with a luminous flux of between 3 and 9 lumens toward at least one neuroanatomical brain structure of a user for a duration of between 6 and 13 minutes. 